May 2012 Clinical Advisor

THE CLINICAL ADVISOR • MAY 2012

A FORUM FOR NURSE PRACTITIONERS

NEWSLINE

■ Aspirin reduces cancer risk ■ Babesiosis on the rise ■ Viral vs. bacterial sinusitis ADVISOR FORUM

■ Drug-testing a teenager ■ Contraception after 50 ■ Calming a bleeding child LEGAL ADVISOR

Was a clinician’s dismissal racially motivated?

✶ FREE CE COURSES!

■ Dermatology Clinic

BLUE MACULES TURN INTO PATCHES PAGE 59

■ Dermatologic Look-Alikes

VOLUME 15, NUMBER 5

FACIAL RASH ITCHES AND BURNS PAGE 65 W Where do you rank iin our Salary Survey?

To find out the results, T tturn to page 33.

| M AY 2 01 2 | www.ClinicalAdvisor.com

CE: OLDER ADULTS TAKING

HAART MEDS HAART meds may affect digestion, insulin resistance, and bone density.

When a hug hurts, LYRICA® (pregabalin) can make a difference in reducing Fibromyalgia pain.

Access downloadable resources for managing Fibromyalgia and learn more about LYRICA at www.FMMGMT.com LYRICA is indicated for the management of Fibromyalgia in adults with respiratory compromise requiring emergency treatment.

18 years and older.

Discontinue LYRICA immediately in patients with these symptoms.

Antiepileptic drugs (AEDs) including LYRICA increase the risk of suicidal thoughts or behavior in patients taking AEDs for any LYRICA is contraindicated in patients with known hypersensitivity indication. Monitor patients treated with any AED for any indication to pregabalin or any of its other components. There have been for the emergence or worsening of depression, suicidal thoughts postmarketing reports of hypersensitivity in patients shortly after or behavior, and/or any unusual changes in mood or behavior. initiation of treatment with LYRICA. Adverse reactions included skin Pooled analyses showed clinical trial patients taking an AED had redness, blisters, hives, rash, dyspnea, and wheezing. Discontinue approximately twice the risk of suicidal thoughts or behavior than LYRICA immediately in patients with these symptoms. placebo-treated patients, and estimated the incidence rate of There have been postmarketing reports of angioedema in patients suicidal behavior or ideation was approximately one patient for during initial and chronic treatment with LYRICA. Specific symptoms every 530 patients treated with an AED. included swelling of the face, mouth (tongue, lips, and gums), and neck The most common adverse reactions across all LYRICA clinical (throat and larynx). There were reports of life-threatening angioedema trials are dizziness, somnolence, dry mouth, edema, blurred vision, Selected safety information:

PBP455517-01

02-08912D_R1_LYR_FM_HUG_JA.indd 1-2

weight ga increased concentra

Inform pat impair the driving or experience motor func

Higher fre patients t drugs. Exe who are ta angiotensi be at incre

© 2012 Pfizer I

algia

treatment. ptoms.

e the risk Ds for any indication l thoughts behavior. n AED had avior than ce rate of patient for

CA clinical red vision,

weight gain, constipation, euphoric mood, balance disorder, when using LYRICA in patients who have had a previous episode increased appetite, and thinking abnormal (primarily difficulty with of angioedema. concentration/attention).

Patients with a history of drug or alcohol abuse may have a higher Inform patients taking LYRICA that dizziness and somnolence may chance of misuse or abuse of LYRICA. impair their ability to perform potentially hazardous tasks such as Withdraw LYRICA gradually over a minimum of 1 week. Discontinue driving or operating complex machinery until they have sufficient LYRICA immediately in patients with symptoms of hypersensitivity experience with LYRICA to determine its effect on cognitive and or angioedema. motor function.

For Full Prescribing Information and Medication Guide, Higher frequency of weight gain and edema was observed in please visit www.FMMGMT.com. patients taking both LYRICA and thiazolidinedione antidiabetic drugs. Exercise caution when coadministering these drugs. Patients Please see Brief Summary of Prescribing Information on adjacent pages. who are taking other drugs associated with angioedema such as angiotensin-converting enzyme inhibitors (ACE inhibitors) may For more info, scan this QR code with be at increased risk of developing angioedema. Exercise caution your smartphone. © 2012 Pfizer Inc.

All rights reserved.

April 2012

4/4/12 8:58 PM

LYRICA® (pregabalin) CAPSULES BRIEF SUMMARY: For full prescribing information, see package insert.

INDICATION AND USAGE LYRICA is indicated for: • Management of neuropathic pain associated with diabetic peripheral neuropathy DOSAGE AND ADMINISTRATION LYRICA is given orally with or without food. When discontinuing LYRICA, taper gradually over a minimum of 1 week.

Neuropathic pain associated with diabetic peripheral neuropathy: • Administer in 3 divided doses per day • Begin dosing at 150 mg/day • May be increased to a maximum of 300 mg/day within 1 week • Dose should be adjusted for patients with reduced renal function Patients with Renal Impairment In view of dose-dependent adverse reactions and since LYRICA is eliminated primarily by renal excretion, adjust the dose in patients with reduced renal function. Base the dose adjustment in patients with renal impairment on creatinine clearance (CLcr), as indicated in Table 1. To use this dosing table, an estimate of the patient’s CLcr in mL/min is needed. CLcr in mL/min may be estimated from serum creatinine (mg/dL) determination using the Cockcroft and Gault equation: [140 - age (years)] x weight (kg) CLCr =

(x 0.85 for female patients) 72 x serum creatinine (mg/dL) Next, refer to the Dosage and Administration section to determine the recommended total daily dose based on indication, for a patient with normal renal function (CLcr ≥60 mL/min). Then refer to Table 1 to determine the corresponding renal adjusted dose.

(For example: A patient initiating LYRICA therapy for postherpetic neuralgia with normal renal function (CLcr ≥60 mL/min), receives a total daily dose of 150 mg/day pregabalin. Therefore, a renal impaired patient with a CLcr of 50 mL/min would receive a total daily dose of 75 mg/day pregabalin administered in two or three divided doses.)

For patients undergoing hemodialysis, adjust the pregabalin daily dose based on renal function. In addition to the daily dose adjustment, administer a supplemental dose immediately following every 4-hour hemodialysis treatment (see Table 1).

Table 1. Pregabalin Dosage Adjustment Based on Renal Function Creatinine Clearance Total Pregabalin Daily Dose (mg/day)* (CLcr) (mL/min) ≥60 150 300 450

Dose Regimen 600

BID or TID

30–60

75

150

225

300

BID or TID

15–30

25–50

75

100–150

150

QD or BID

<15

25

25–50

50–75

75

QD

Supplementary dosage following hemodialysis (mg)† Patients on the 25 mg QD regimen: take one supplemental dose of 25 mg or 50 mg Patients on the 25–50 mg QD regimen: take one supplemental dose of 50 mg or 75 mg Patients on the 50–75 mg QD regimen: take one supplemental dose of 75 mg or 100 mg Patients on the 75 mg QD regimen: take one supplemental dose of 100 mg or 150 mg TID = Three divided doses; BID = Two divided doses; QD = Single daily dose. *Total daily dose (mg/day) should be divided as indicated by dose regimen to provide mg/dose. †Supplementary dose is a single additional dose.

CONTRAINDICATIONS LYRICA is contraindicated in patients with known hypersensitivity to pregabalin or any of its components. Angioedema and hypersensitivity reactions have occurred in patients receiving pregabalin therapy.

WARNINGS AND PRECAUTIONS Angioedema There have been postmarketing reports of angioedema in patients during initial and chronic treatment with LYRICA. Specific symptoms included swelling of the face, mouth (tongue, lips, and gums), and neck (throat and larynx).

There were reports of life-threatening angioedema with respiratory compromise requiring emergency treatment.

Discontinue LYRICA immediately in patients with these symptoms. Exercise caution when prescribing LYRICA to patients who have had a previous episode of angioedema. In addition, patients who are taking other drugs associated with angioedema (e.g., angiotensin converting enzyme inhibitors [ACE-inhibitors]) may be at increased risk of developing angioedema. Hypersensitivity There have been postmarketing reports of hypersensitivity in patients shortly after initiation of treatment with LYRICA. Adverse reactions included skin redness, blisters, hives, rash, dyspnea, and wheezing.

Discontinue LYRICA immediately in patients with these symptoms. Withdrawal of Antiepileptic Drugs (AEDs) As with all AEDs, withdraw LYRICA gradually to minimize the potential of increased seizure frequency in patients with seizure disorders. If LYRICA is discontinued, taper the drug gradually over a minimum of 1 week. Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including LYRICA, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Monitor patients treated with any AED for any indication for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Pooled analyses of 199 placebocontrolled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI: 1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebotreated patients, but the number is too small to allow any conclusion about drug effect on suicide. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication.

The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. Table 2 shows absolute and relative risk by indication for all evaluated AEDs. Table 2 Risk by indication for antiepileptic drugs in the pooled analysis Indication Placebo Patients Drug Patients Relative Risk: with Events Per with Events Per Incidence of Events 1000 Patients 1000 Patients in Drug Patients/Incidence in Placebo Patients Epilepsy 1.0 3.4 3.5 Psychiatric 5.7 8.5 1.5 Other 1.0 1.8 1.9 Total 2.4 4.3 1.8

Risk Difference: Additional Drug Patients with Events Per 1000 Patients 2.4 2.9 0.9 1.9

The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. Anyone considering prescribing LYRICA or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. Inform patients, their caregivers, and families that LYRICA and other AEDs increase the risk of suicidal thoughts and behavior and advise them of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts,

behavior, or thoughts about self-harm. Report behaviors of concern immediately to healthcare providers. Peripheral Edema LYRICA treatment may cause peripheral edema. In short-term trials of patients without clinically significant heart or peripheral vascular disease, there was no apparent association between peripheral edema and cardiovascular complications such as hypertension or congestive heart failure. Peripheral edema was not associated with laboratory changes suggestive of deterioration in renal or hepatic function. In controlled clinical trials the incidence of peripheral edema was 6% in the LYRICA group compared with 2% in the placebo group. In controlled clinical trials, 0.5% of LYRICA patients and 0.2% placebo patients withdrew due to peripheral edema. Higher frequencies of weight gain and peripheral edema were observed in patients taking both LYRICA and a thiazolidinedione antidiabetic agent compared to patients taking either drug alone. The majority of patients using thiazolidinedione antidiabetic agents in the overall safety database were participants in studies of pain associated with diabetic peripheral neuropathy. In this population, peripheral edema was reported in 3% (2/60) of patients who were using thiazolidinedione antidiabetic agents only, 8% (69/859) of patients who were treated with LYRICA only, and 19% (23/120) of patients who were on both LYRICA and thiazolidinedione antidiabetic agents. Similarly, weight gain was reported in 0% (0/60) of patients on thiazolidinediones only; 4% (35/859) of patients on LYRICA only; and 7.5% (9/120) of patients on both drugs. As the thiazolidinedione class of antidiabetic drugs can cause weight gain and/or fluid retention, possibly exacerbating or leading to heart failure, exercise caution when coadministering LYRICA and these agents. Because there are limited data on congestive heart failure patients with New York Heart Association (NYHA) Class III or IV cardiac status, exercise caution when using LYRICA in these patients.

Dizziness and Somnolence LYRICA may cause dizziness and somnolence. Inform patients that LYRICA-related dizziness and somnolence may impair their ability to perform tasks such as driving or operating machinery. In the LYRICA controlled trials, dizziness was experienced by 31% of LYRICA-treated patients compared to 9% of placebo-treated patients; somnolence was experienced by 22% of LYRICA-treated patients compared to 7% of placebo-treated patients. Dizziness and somnolence generally began shortly after the initiation of LYRICA therapy and occurred more frequently at higher doses. Dizziness and somnolence were the adverse reactions most frequently leading to withdrawal (4% each) from controlled studies. In LYRICA-treated patients reporting these adverse reactions in short-term, controlled studies, dizziness persisted until the last dose in 30% and somnolence persisted until the last dose in 42% of patients. Weight Gain LYRICA treatment may cause weight gain. In LYRICA controlled clinical trials of up to 14 weeks, a gain of 7% or more over baseline weight was observed in 9% of LYRICA-treated patients and 2% of placebo-treated patients. Few patients treated with LYRICA (0.3%) withdrew from controlled trials due to weight gain. LYRICA associated weight gain was related to dose and duration of exposure, but did not appear to be associated with baseline BMI, gender, or age. Weight gain was not limited to patients with edema [see Warnings and Precautions, Peripheral Edema]. Although weight gain was not associated with clinically important changes in blood pressure in short-term controlled studies, the long-term cardiovascular effects of LYRICA-associated weight gain are unknown. Among diabetic patients, LYRICA-treated patients gained an average of 1.6 kg (range: -16 to 16 kg), compared to an average 0.3 kg (range: -10 to 9 kg) weight gain in placebo patients.

In a cohort of 333 diabetic patients who received LYRICA for at least 2 years, the average weight gain was 5.2 kg. While the effects of LYRICA-associated weight gain on glycemic control have not been systematically assessed, in controlled and longer-term open label clinical trials with diabetic patients, LYRICA treatment did not appear to be associated with loss of glycemic control (as measured by HbA1C). Abrupt or Rapid Discontinuation Following abrupt or rapid discontinuation of LYRICA, some patients reported symptoms including insomnia, nausea, headache, and diarrhea. Taper LYRICA gradually over a minimum of 1 week rather than discontinuing the drug abruptly. Tumorigenic Potential In standard preclinical in vivo lifetime carcinogenicity studies of LYRICA, an unexpectedly high incidence of hemangiosarcoma was identified in two different strains of mice [see Nonclinical Toxicology, Carcinogenesis, Mutagenesis, Impairment of Fertility]. The clinical significance of this finding is unknown. Clinical experience during LYRICA’s premarketing development provides no direct means to assess its potential for inducing tumors in humans. In clinical studies across various patient populations, comprising 6396 patient-years of exposure in patients >12 years of age, new or worsening-preexisting tumors were reported in 57 patients. Without knowledge of the background incidence and recurrence in similar populations not treated with LYRICA, it is impossible to know whether the incidence seen in these cohorts is or is not affected by treatment.

Ophthalmological Effects In controlled studies, a higher proportion of patients treated with LYRICA reported blurred vision (7%) than did patients treated with placebo (2%), which resolved in a majority of cases with continued dosing. Less than 1% of patients discontinued LYRICA treatment due to vision-related events (primarily blurred vision). Prospectively planned ophthalmologic testing, including visual acuity testing, formal visual field testing and dilated funduscopic examination, was performed in over 3600 patients. In these patients, visual acuity was reduced in 7% of patients treated with LYRICA, and 5% of placebo-treated patients. Visual field changes were detected in 13% of LYRICA-treated, and 12% of placebo-treated patients. Funduscopic changes were observed in 2% of LYRICA-treated and 2% of placebo-treated patients. Although the clinical significance of the ophthalmologic findings is unknown, inform patients to notify their physician if changes in vision occur. If visual disturbance persists, consider further assessment. Consider more frequent assessment for patients who are already routinely monitored for ocular conditions. Creatine Kinase Elevations LYRICA treatment was associated with creatine kinase elevations. Mean changes in creatine kinase from baseline to the maximum value were 60 U/L for LYRICA-treated patients and 28 U/L for the placebo patients. In all controlled trials across multiple patient populations, 1.5% of patients on LYRICA and 0.7% of placebo patients had a value of creatine kinase at least three times the upper limit of normal. Three LYRICA-treated subjects had events reported as rhabdomyolysis in premarketing clinical trials. The relationship between these myopathy events and LYRICA is not completely understood because the cases had documented factors that may have caused or contributed to these events. Instruct patients to promptly report unexplained muscle pain, tenderness, or weakness, particularly if these muscle symptoms are accompanied by malaise or fever. Discontinue treatment with LYRICA if myopathy is diagnosed or suspected or if markedly elevated creatine kinase levels occur. Decreased Platelet Count LYRICA treatment was associated with a decrease in platelet count. LYRICAtreated subjects experienced a mean maximal decrease in platelet count of 20 x 103/µL, compared to 11 x 10 3/µL in placebo patients. In the overall database of controlled trials, 2% of placebo patients and 3% of LYRICA patients experienced a potentially clinically significant decrease in platelets, defined as 20% below baseline value and <150 x 10 3/µL. A single LYRICA treated subject developed severe thrombocytopenia with a platelet count less than 20 x 103/µL. In randomized controlled trials, LYRICA was not associated with an increase in bleeding-related adverse reactions. PR Interval Prolongation LYRICA treatment was associated with PR interval prolongation. In analyses of clinical trial ECG data, the mean PR interval increase was 3–6 msec at LYRICA doses ≥300 mg/day. This mean change difference was not associated with an increased risk of PR increase ≥25% from baseline, an increased percentage of subjects with on-treatment PR >200 msec, or an increased risk of adverse reactions of second or third degree AV block. Subgroup analyses did not identify an increased risk of PR prolongation in patients with baseline PR prolongation or in patients taking other PR prolonging medications. However, these analyses cannot be considered definitive because of the limited number of patients in these categories.

ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In all controlled and uncontrolled trials across various patient populations during the premarketing development of LYRICA, more than 10,000 patients have received LYRICA. Approximately 5000 patients were treated for 6 months or more, over 3100 patients were treated for 1 year or longer, and over 1400 patients were treated for at least 2 years.

Adverse Reactions Most Commonly Leading to Discontinuation in All Premarketing Controlled Clinical Studies In premarketing controlled trials of all populations combined, 14% of patients treated with LYRICA and 7% of patients treated with placebo discontinued prematurely due to adverse reactions. In the LYRICA treatment group, the adverse reactions most frequently leading to discontinuation were dizziness (4%) and somnolence (3%). In the placebo group, 1% of patients withdrew due to dizziness and <1% withdrew due to somnolence. Other adverse reactions that led to discontinuation from controlled trials more frequently in the LYRICA group compared to the placebo group were ataxia, confusion, asthenia, thinking abnormal, blurred vision, incoordination, and peripheral edema (1% each).

Most Common Adverse Reactions in All Premarketing Controlled Clinical Studies In premarketing controlled trials of all patient populations combined, dizziness, somnolence, dry mouth, edema, blurred vision, weight gain, and “thinking abnormal” (primarily difficulty with concentration/attention) were more commonly reported by subjects treated with LYRICA than by subjects treated with placebo (≥5% and twice the rate of that seen in placebo).

Controlled Studies with Neuropathic Pain Associated with Diabetic Peripheral Neuropathy Adverse Reactions Leading to Discontinuation In clinical trials in patients with neuropathic pain associated with diabetic peripheral neuropathy, 9% of patients treated with LYRICA and 4% of patients treated with placebo discontinued prematurely due to adverse reactions. In the LYRICA treatment group, the most common reasons for discontinuation due to adverse reactions were dizziness (3%) and somnolence (2%). In comparison, <1% of placebo patients withdrew due to dizziness and somnolence. Other reasons for discontinuation from the trials, occurring with greater frequency in the LYRICA group than in the placebo group, were asthenia, confusion, and peripheral edema. Each of these events led to withdrawal in approximately 1% of patients.

Most Common Adverse Reactions Table 3 lists all adverse reactions, regardless of causality, occurring in ≥1% of patients with neuropathic pain associated with diabetic neuropathy in the combined LYRICA group for which the incidence was greater in this combined LYRICA group than in the placebo group. A majority of pregabalin-treated patients in clinical studies had adverse reactions with a maximum intensity of “mild” or “moderate”.

Table 3 Treatment-emergent adverse reaction incidence in controlled trials in Neuropathic Pain Associated with Diabetic Peripheral Neuropathy (Events in at least 1% of all LYRICA-treated patients and at least numerically more in all LYRICA than in the placebo group) 75 mg/d 150 mg/d 300 mg/d 600 mg/d All PGB* Placebo Body System [N=77] [N=212] [N=321] [N=369] [N=979] [N=459] - Preferred term % % % % % % Body as a whole Asthenia 4 2 4 7 5 2 Accidental injury 5 2 2 6 4 3 Back pain 0 2 1 2 2 0 Chest pain 4 1 1 2 2 1 Face edema 0 1 1 2 1 0 Digestive system Dry mouth 3 2 5 7 5 1 Constipation 0 2 4 6 4 2 Flatulence 3 0 2 3 2 1 Metabolic and nutritional disorders Peripheral edema 4 6 9 12 9 2 Weight gain 0 4 4 6 4 0 Edema 0 2 4 2 2 0 Hypoglycemia 1 3 2 1 2 1 Nervous system Dizziness 8 9 23 29 21 5 Somnolence 4 6 13 16 12 3 Neuropathy 9 2 2 5 4 3 Ataxia 6 1 2 4 3 1 Vertigo 1 2 2 4 3 1 Confusion 0 1 2 3 2 1 Euphoria 0 0 3 2 2 0 Incoordination 1 0 2 2 2 0 1 0 1 3 2 0 Thinking abnormal† Tremor 1 1 1 2 1 0 Abnormal gait 1 0 1 3 1 0 Amnesia 3 1 0 2 1 0 Nervousness 0 1 1 1 1 0 Respiratory system Dyspnea 3 0 2 2 2 1 Special senses 3 1 3 6 4 2 Blurry vision‡ Abnormal vision 1 0 1 1 1 0 *PGB: pregabalin † Thinking abnormal primarily consists of events related to difficulty with concentration/attention but also includes events related to cognition and language problems and slowed thinking. ‡ Investigator term; summary level term is amblyopia.

Other Adverse Reactions Observed During the Clinical Studies of LYRICA Following is a list of treatment-emergent adverse reactions reported by patients treated with LYRICA during all clinical trials. The listing does not include those events already listed in the previous tables or elsewhere in labeling, those events for which a drug cause was remote, those events which were so general as to be uninformative, and those events reported only once which did not have a substantial probability of being acutely life-threatening. Events are categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse reactions are those occurring on one or more occasions in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions are those occurring in fewer than 1/1000 patients. Events of major clinical importance are described in the Warnings and Precautions section. Body as a Whole – Frequent: Abdominal pain, Allergic reaction, Fever; Infrequent: Abscess, Cellulitis, Chills, Malaise, Neck rigidity, Overdose, Pelvic pain, Photosensitivity reaction; Rare: Anaphylactoid reaction, Ascites, Granuloma, Hangover effect, Intentional Injury, Retroperitoneal Fibrosis, Shock. Cardiovascular System – Infrequent: Deep thrombophlebitis, Heart failure, Hypotension, Postural hypotension, Retinal vascular disorder, Syncope; Rare: ST Depressed, Ventricular Fibrillation. Digestive System – Frequent: Gastroenteritis, Increased appetite; Infrequent: Cholecystitis, Cholelithiasis, Colitis, Dysphagia, Esophagitis, Gastritis, Gastrointestinal hemorrhage, Melena, Mouth ulceration, Pancreatitis, Rectal hemorrhage, Tongue edema; Rare: Aphthous stomatitis, Esophageal Ulcer, Periodontal abscess. Hemic and Lymphatic System – Frequent: Ecchymosis; Infrequent: Anemia, Eosinophilia, Hypochromic anemia, Leukocytosis, Leukopenia, Lymphadenopathy, Thrombocytopenia; Rare: Myelofibrosis, Polycythemia, Prothrombin decreased, Purpura, Thrombocythemia. Metabolic and Nutritional Disorders – Rare: Glucose Tolerance Decreased, Urate Crystalluria.

Musculoskeletal System – Frequent: Arthralgia, Leg cramps, Myalgia, Myasthenia; Infrequent: Arthrosis; Rare: Chondrodystrophy, Generalized Spasm. Nervous System – Frequent: Anxiety, Depersonalization, Hypertonia, Hypesthesia, Libido decreased, Nystagmus, Paresthesia, Stupor, Twitching; Infrequent: Abnormal dreams, Agitation, Apathy, Aphasia, Circumoral paresthesia, Dysarthria, Hallucinations, Hostility, Hyperalgesia, Hyperesthesia, Hyperkinesia, Hypokinesia, Hypotonia, Libido increased, Myoclonus, Neuralgia; Rare: Addiction, Cerebellar syndrome, Cogwheel rigidity, Coma, Delirium, Delusions, Dysautonomia, Dyskinesia, Dystonia, Encephalopathy, Extrapyramidal syndrome, Guillain-Barré syndrome, Hypalgesia, Intracranial hypertension, Manic reaction, Paranoid reaction, Peripheral neuritis, Personality disorder, Psychotic depression, Schizophrenic reaction, Sleep disorder, Torticollis, Trismus. Respiratory System – Rare: Apnea, Atelectasis, Bronchiolitis, Hiccup, Laryngismus, Lung edema, Lung fibrosis, Yawn. Skin and Appendages – Frequent: Pruritus; Infrequent: Alopecia, Dry skin, Eczema, Hirsutism, Skin ulcer, Urticaria, Vesiculobullous rash; Rare: Angioedema, Exfoliative dermatitis, Lichenoid dermatitis, Melanosis, Nail Disorder, Petechial rash, Purpuric rash, Pustular rash, Skin atrophy, Skin necrosis, Skin nodule, Stevens-Johnson syndrome, Subcutaneous nodule. Special senses – Frequent: Conjunctivitis, Diplopia, Otitis media, Tinnitus; Infrequent: Abnormality of accommodation, Blepharitis, Dry eyes, Eye hemorrhage, Hyperacusis, Photophobia, Retinal edema, Taste loss, Taste perversion; Rare: Anisocoria, Blindness, Corneal ulcer, Exophthalmos, Extraocular palsy, Iritis, Keratitis, Keratoconjunctivitis, Miosis, Mydriasis, Night blindness, Ophthalmoplegia, Optic atrophy, Papilledema, Parosmia, Ptosis, Uveitis. Urogenital System – Frequent: Anorgasmia, Impotence, Urinary frequency, Urinary incontinence; Infrequent: Abnormal ejaculation, Albuminuria, Amenorrhea, Dysmenorrhea, Dysuria, Hematuria, Kidney calculus, Leukorrhea, Menorrhagia, Metrorrhagia, Nephritis, Oliguria, Urinary retention, Urine abnormality; Rare: Acute kidney failure, Balanitis, Bladder Neoplasm, Cervicitis, Dyspareunia, Epididymitis, Female lactation, Glomerulitis, Ovarian disorder, Pyelonephritis.

Comparison of Gender and Race The overall adverse event profile of pregabalin was similar between women and men.

There are insufficient data to support a statement regarding the distribution of adverse experience reports by race.

Post-marketing Experience The following adverse reactions have been identified during postapproval use of LYRICA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Nervous System Disorders – Headache. Gastrointestinal Disorders – Nausea, Diarrhea. Reproductive System and Breast Disorders – Gynecomastia, Breast Enlargement.

DRUG INTERACTIONS Since LYRICA is predominantly excreted unchanged in the urine, undergoes negligible metabolism in humans (<2% of a dose recovered in urine as metabolites), and does not bind to plasma proteins, its pharmacokinetics are unlikely to be affected by other agents through metabolic interactions or protein binding displacement. In vitro and in vivo studies showed that LYRICA is unlikely to be involved in significant pharmacokinetic drug interactions. Specifically, there are no pharmacokinetic interactions between pregabalin and the following antiepileptic drugs: carbamazepine, valproic acid, lamotrigine, phenytoin, phenobarbital, and topiramate. Important pharmacokinetic interactions would also not be expected to occur between LYRICA and commonly used antiepileptic drugs.

Pharmacodynamics Multiple oral doses of LYRICA were co-administered with oxycodone, lorazepam, or ethanol. Although no pharmacokinetic interactions were seen, additive effects on cognitive and gross motor functioning were seen when LYRICA was co-administered with these drugs. No clinically important effects on respiration were seen.

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C. Increased incidences of fetal structural abnormalities and other manifestations of developmental toxicity, including lethality, growth retardation, and nervous and reproductive system functional impairment, were observed in the offspring of rats and rabbits given pregabalin during pregnancy, at doses that produced plasma pregabalin exposures (AUC) ≥5 times human exposure at the maximum recommended dose (MRD) of 600 mg/day. When pregnant rats were given pregabalin (500, 1250, or 2500 mg/kg) orally throughout the period of organogenesis, incidences of specific skull alterations attributed to abnormally advanced ossification (premature fusion of the jugal and nasal sutures) were increased at ≥1250 mg/kg, and incidences of skeletal variations and retarded ossification were increased at all doses. Fetal body weights were decreased at the highest dose. The low dose in this study was associated with a plasma

exposure (AUC) approximately 17 times human exposure at the MRD of 600 mg/day. A no-effect dose for rat embryo-fetal developmental toxicity was not established. When pregnant rabbits were given LYRICA (250, 500, or 1250 mg/kg) orally throughout the period of organogenesis, decreased fetal body weight and increased incidences of skeletal malformations, visceral variations, and retarded ossification were observed at the highest dose. The no-effect dose for developmental toxicity in rabbits (500 mg/kg) was associated with a plasma exposure approximately 16 times human exposure at the MRD. In a study in which female rats were dosed with LYRICA (50, 100, 250, 1250, or 2500 mg/kg) throughout gestation and lactation, offspring growth was reduced at ≥100 mg/kg and offspring survival was decreased at ≥250 mg/kg. The effect on offspring survival was pronounced at doses ≥1250 mg/kg, with 100% mortality in high-dose litters. When offspring were tested as adults, neurobehavioral abnormalities (decreased auditory startle responding) were observed at ≥250 mg/kg and reproductive impairment (decreased fertility and litter size) was seen at 1250 mg/kg. The no-effect dose for pre- and postnatal developmental toxicity in rats (50 mg/kg) produced a plasma exposure approximately 2 times human exposure at the MRD. There are no adequate and well-controlled studies in pregnant women. Use LYRICA during pregnancy only if the potential benefit justifies the potential risk to the fetus. To provide information regarding the effects of in utero exposure to LYRICA, physicians are advised to recommend that pregnant patients taking LYRICA enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www. aedpregnancyregistry.org/. Labor and Delivery The effects of LYRICA on labor and delivery in pregnant women are unknown. In the prenatal-postnatal study in rats, pregabalin prolonged gestation and induced dystocia at exposures ≥50 times the mean human exposure (AUC (0–24) of 123 µg•hr/mL) at the maximum recommended clinical dose of 600 mg/day.

Nursing Mothers It is not known if pregabalin is excreted in human milk; it is, however, present in the milk of rats.

Because many drugs are excreted in human milk, and because of the potential for tumorigenicity shown for pregabalin in animal studies, decide whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and efficacy of pregabalin in pediatric patients have not been established.

In studies in which pregabalin (50 to 500 mg/kg) was orally administered to young rats from early in the postnatal period (Postnatal Day 7) through sexual maturity, neurobehavioral abnormalities (deficits in learning and memory, altered locomotor activity, decreased auditory startle responding and habituation) and reproductive impairment (delayed sexual maturation and decreased fertility in males and females) were observed at doses ≥50 mg/kg. The neurobehavioral changes of acoustic startle persisted at ≥250 mg/kg and locomotor activity and water maze performance at ≥500 mg/kg in animals tested after cessation of dosing and, thus, were considered to represent long-term effects. The low effect dose for developmental neurotoxicity and reproductive impairment in juvenile rats (50 mg/kg) was associated with a plasma pregabalin exposure (AUC) approximately equal to human exposure at the maximum recommended dose of 600 mg/day. A no-effect dose was not established. Geriatric Use In controlled clinical studies of LYRICA in neuropathic pain associated with diabetic peripheral neuropathy, 246 patients were 65 to 74 years of age, and 73 patients were 75 years of age or older. In controlled clinical studies of LYRICA in neuropathic pain associated with postherpetic neuralgia, 282 patients were 65 to 74 years of age, and 379 patients were 75 years of age or older. No overall differences in safety and efficacy were observed between these patients and younger patients. In controlled clinical studies of LYRICA in fibromyalgia, 106 patients were 65 years of age or older. Although the adverse reaction profile was similar between the two age groups, the following neurological adverse reactions were more frequent in patients 65 years of age or older: dizziness, vision blurred, balance disorder, tremor, confusional state, coordination abnormal, and lethargy. LYRICA is known to be substantially excreted by the kidney, and the risk of toxic reactions to LYRICA may be greater in patients with impaired renal function. Because LYRICA is eliminated primarily by renal excretion, adjust the dose for elderly patients with renal impairment.

DRUG ABUSE AND DEPENDENCE Controlled Substance LYRICA is a Schedule V controlled substance. LYRICA is not known to be active at receptor sites associated with drugs of abuse. As with any CNS active drug, carefully evaluate patients for history of drug abuse and observe them for signs of LYRICA misuse or abuse (e.g., development of tolerance, dose escalation, drug-seeking behavior).

Abuse In a study of recreational users (N=15) of sedative/hypnotic drugs, including alcohol, LYRICA (450 mg, single dose) received subjective ratings of “good drug effect,” “high” and “liking” to a degree that was similar to diazepam (30 mg, single dose). In controlled clinical studies in over 5500 patients, 4% of LYRICA-treated patients and 1% of placebo-treated patients overall reported euphoria as an adverse reaction, though in some patient populations studied, this reporting rate was higher and ranged from 1 to 12%. Dependence In clinical studies, following abrupt or rapid discontinuation of LYRICA, some patients reported symptoms including insomnia, nausea, headache or diarrhea [see Warnings and Precautions, Abrupt or Rapid Discontinuation], suggestive of physical dependence.

OVERDOSAGE Signs, Symptoms and Laboratory Findings of Acute Overdosage in Humans There is limited experience with overdose of LYRICA. The highest reported accidental overdose of LYRICA during the clinical development program was 8000 mg, and there were no notable clinical consequences. Treatment or Management of Overdose There is no specific antidote for overdose with LYRICA. If indicated, elimination of unabsorbed drug may be attempted by emesis or gastric lavage; observe usual precautions to maintain the airway. General supportive care of the patient is indicated including monitoring of vital signs and observation of the clinical status of the patient. Contact a Certified Poison Control Center for up-to-date information on the management of overdose with LYRICA. Although hemodialysis has not been performed in the few known cases of overdose, it may be indicated by the patient’s clinical state or in patients with significant renal impairment.

Standard hemodialysis procedures result in significant clearance of pregabalin (approximately 50% in 4 hours).

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis A dose-dependent increase in the incidence of malignant vascular tumors (hemangiosarcomas) was observed in two strains of mice (B6C3F1 and CD-1) given pregabalin (200, 1000, or 5000 mg/kg) in the diet for two years. Plasma pregabalin exposure (AUC) in mice receiving the lowest dose that increased hemangiosarcomas was approximately equal to the human exposure at the maximum recommended dose (MRD) of 600 mg/day. A no-effect dose for induction of hemangiosarcomas in mice was not established. No evidence of carcinogenicity was seen in two studies in Wistar rats following dietary administration of pregabalin for two years at doses (50, 150, or 450 mg/kg in males and 100, 300, or 900 mg/kg in females) that were associated with plasma exposures in males and females up to approximately 14 and 24 times, respectively, human exposure at the MRD. Mutagenesis Pregabalin was not mutagenic in bacteria or in mammalian cells in vitro, was not clastogenic in mammalian systems in vitro and in vivo, and did not induce unscheduled DNA synthesis in mouse or rat hepatocytes. Impairment of Fertility In fertility studies in which male rats were orally administered pregabalin (50 to 2500 mg/kg) prior to and during mating with untreated females, a number of adverse reproductive and developmental effects were observed. These included decreased sperm counts and sperm motility, increased sperm abnormalities, reduced fertility, increased preimplantation embryo loss, decreased litter size, decreased fetal body weights, and an increased incidence of fetal abnormalities. Effects on sperm and fertility parameters were reversible in studies of this duration (3–4 months). The no-effect dose for male reproductive toxicity in these studies (100 mg/kg) was associated with a plasma pregabalin exposure (AUC) approximately 3 times human exposure at the maximum recommended dose (MRD) of 600 mg/day. In addition, adverse reactions on reproductive organ (testes, epididymides) histopathology were observed in male rats exposed to pregabalin (500 to 1250 mg/kg) in general toxicology studies of four weeks or greater duration. The no-effect dose for male reproductive organ histopathology in rats (250 mg/kg) was associated with a plasma exposure approximately 8 times human exposure at the MRD. In a fertility study in which female rats were given pregabalin (500, 1250, or 2500 mg/kg) orally prior to and during mating and early gestation, disrupted estrous cyclicity and an increased number of days to mating were seen at all doses, and embryolethality occurred at the highest dose. The low dose in this study produced a plasma exposure approximately 9 times that in humans receiving the MRD. A no-effect dose for female reproductive toxicity in rats was not established.

Human Data In a double-blind, placebo-controlled clinical trial to assess the effect of pregabalin on sperm motility, 30 healthy male subjects were exposed to pregabalin at a dose of 600 mg/day. After 3 months of treatment (one complete sperm cycle), the difference between placebo- and pregabalin-treated subjects in mean percent sperm with normal motility was <4% and neither group had a mean change from baseline of more than 2%. Effects on other male reproductive parameters in humans have not been adequately studied.

Animal Toxicology and/or Pharmacology Dermatopathy Skin lesions ranging from erythema to necrosis were seen in repeated-dose toxicology studies in both rats and monkeys. The etiology of these skin lesions is unknown. At the maximum recommended human dose (MRD) of 600 mg/day, there is a 2-fold safety margin for the dermatological lesions.

The more severe dermatopathies involving necrosis were associated with pregabalin exposures (as expressed by plasma AUCs) of approximately 3 to 8 times those achieved in humans given the MRD. No increase in incidence of skin lesions was observed in clinical studies. Ocular Lesions Ocular lesions (characterized by retinal atrophy [including loss of photoreceptor cells] and/or corneal inflammation/mineralization) were observed in two lifetime carcinogenicity studies in Wistar rats. These findings were observed at plasma pregabalin exposures (AUC) ≥2 times those achieved in humans given the maximum recommended dose of 600 mg/day. A no-effect dose for ocular lesions was not established. Similar lesions were not observed in lifetime carcinogenicity studies in two strains of mice or in monkeys treated for 1 year.

LAB-0294-21.0 June 2011

PBP01873/291898-01

© 2011 Pfizer Inc.

All rights reserved.

GET INVOLVED AT

ClinicalAdvisor.com!

Editor Joe Kopcha, editor@clinicaladvisor.com Managing editor Marina Galanakis Senior editor Delicia Yard Web editor Nicole Blazek Contributing editors Bruce D. Askey, MSN, CRNP; Rebecca H. Bryan, APRN, CNP; Eileen F. Campbell, MSN, CRNP; Philip R. Cohen, MD; Deborah L. Cross, MPH, CRNP, ANP-BC; Sharon Dudley-Brown, PhD, FNP-BC; Maria Kidner, DNP, FNP-C; Joan W. Kiely, MSN, CRNP; Debra August King, PhD, PA; Ann W. Latner, JD; Claire B. O’Connell, MPH, PA-C; Kathy Pereira, MSN, FNP-BC; Sherril Sego, FNP, DNP; Julee B. Waldrop, MS, PNP; Kim Zuber, PA-C Art director Andrew Bass Group art director, Haymarket Medical Jennifer Dvoretz Production director Leslie Carsman Circulation manager Paul Silver Audience development director John Crewe National accounts manager Alison McCauley, 646.638.6098 alison.mccauley@haymarketmedical.com Group publisher Thomas P. Hennessy, 646.638.6085 tom.hennessy@haymarketmedia.com Editorial director Tanya Gregory Vice president, medical magazines and digital products Jim Burke CEO, Haymarket Media Inc. Lee Maniscalco

SUBMIT QUESTIONS & PEARLS Are you stumped? Have no fear — our panel of expert clinicians is ready to help.

Submit your questions to the Advisor Forum at ClinicalAdvisor.com/AdvisorForum Pass it on! Do you have a Clinical Pearl others might find useful? Don’t keep it to yourself. Share it with your colleagues at ClinicalAdvisor.com/ClinicalPearls

TAKE OUR POLLS Find out how your opinion compares with that of your peers on how to handle different clinical situations by visiting ClinicalAdvisor.com/polls

SUBSCRIBE TO WEEKLY E-NEWSLETTERS To stay on top of the latest information on our website, sign up for our regular e-newsletters at ClinicalAdvisor.com/subscribe Inside This Month’s Issue • Latest CME/CE • Informed Consent • Clinical Advisor Spotlight • Derm Dx • Online First

EARN CREDIT WITH CME/CE COURSES Every month, earn up to 1.0 hours of CME/ CE credit by completing the activities found at ClinicalAdvisor.com/CME-CE

All correspondence to: The Clinical Advisor 114 West 26th Street, 4th Floor, New York, NY 10001 For advertising sales, call 646.638.6075.

For reprints, contact Wright’s Reprints at 877.652.5295.

WIND DOWN WITH A LAUGH

Persons appearing in photographs in “Newsline,” “The Legal Advisor,” and “Clinical Challenge” are not the actual individuals mentioned in the articles.They appear for illustrative purposes only.

Now you can see our cartoons online, too.

Treat yourself to a smile or chuckle and view our cartoon slideshows at ClinicalAdvisor.com/ cartoons

“It’s repetitive motion injury for throwing the book at people.”

4 THE CLINICAL ADVISOR • MAY 2012 • www.ClinicalAdvisor.com

© Roy Delgado

The Clinical Advisor® (USPS 017-546, ISSN 1524-7317), Volume 15, Number 5, is published 12 times a year, monthly, for $75.00 per year in the United States; $85.00 in Canada; $110.00 for all other foreign, in U.S. dollars, by Haymarket Media, Inc., 114 West 26th Street, 4th Floor, New York, NY 10001. Single copy: $20 U.S.; $30 foreign. www.ClinicalAdvisor.com. To order or update your paid subscription, call 800.436.9269. Periodicals postage rate paid at New York, NY, and additional mailing offices. POSTMASTER: Send all address changes to:The Clinical Advisor, c/o DMDData Inc., 2340 River Road, Des Plaines, IL 60018. Call 800.430.5450 to change your address or make other subscription inquiries. Requests for subscriptions from outside the United States must be accompanied by payment.

All rights reserved. Reproduction in whole or in part without permission is prohibited.

Copyright © 2012.

CONTENTS M AY 2 0 1 2

NEWS AND COMMENT 18

72

59

23

■ A woman’s blue-gray rash spread from her adbomen to her extremities.

Newsline ■ Aspirin appears to keep cancer at bay ■ Tick-borne disease looks like the flu ■ Check this list before ordering that test ■ And more

■ An elderly woman developed a fi rm, pink nodule on the vertex of her scalp.

63

Alternative Meds Update Rich in antioxidants, tart cherries are used to offset inflammation.

65

CME/CE Dermatologic Look-Alikes OTC treatments provided no relief for two women with bimalar facial rashes.

70

CME/CE Posttest

Commentary

FEATURES

CME/CE Dermatology Clinic

Managing older adults on HAART meds 23

CME/CE HAART meds: Implications for the older adult patient HIV patients are living longer, which means more age-related comorbidities that require other medications as well.

ADVISOR FORUM 33

Salary survey 2012: How are you doing?

The results of our second annual salary survey are in. See how yours compares.

44

Consultations ■ Secondary malignancy following

breast and uterine cancer ■ Drug-testing a teenager without

37

Optimizing technology for diabetes care Follow these strategies to stay current on the latest therapeutic advances.

Derm Dx Read the clinical descriptions, view the images, and make your diagnosis at ClinicalAdvisor.com.

51

Legal Advisor Charges of reverse discrimination fly after a clinician loses her job.

MAKING CONTACT

Follow us on Twitter @ClinicalAdvisor

■ And more

46

DEPARTMENTS 50

permission

Technological advances in diabetes care 37

Does a “butterfly rash” always mean lupus? 65

Like us on Facebook facebook.com/TheClinicalAdvisor

Clinical Pearls ■ Keeping a bleeding child calm ■ Eye-drop application tips ■ Illustrating coronary anatomy

www.ClinicalAdvisor.com

Visit us on the web ClinicalAdvisor.com

Go mobile with us mobile.ClinicalAdvisor.com

EXCLUSIVE TO THE WEB AT

ClinicalAdvisor.com/web-only Web Exclusives

Slideshows

ClinicalAdvisor.com/WebExclusives

ClinicalAdvisor.com/Slideshows

“Five Ss” technique reduces immunization pain Swaddling and other forms of physical distraction reduces pain scores and crying time following routine immunizations for infants aged 2 to 4 months.

Fibromyalgia pain management Fibromyalgia is a syndrome characterized by chronic pain, stiffness, and tenderness of muscles, tendons, and joints without detectable inflammation. Learn more about diagnosis and management with this slideshow.

Obesity costs higher than previously estimated New calculation method estimates higher health-care costs for obesity-related illnesses.

The Waiting Room Official Blog of The Clinical Advisor

Occupational exposures put nurses at risk for miscarriage Exposure to antineoplastic drugs and sterilizing agents increases the risk for spontaneous miscarriage among pregnant nurses.

ClinicalAdvisor.com/Blog Leigh Montejo, MSN, FNP-BC Surviving the early years of clinical practice The ability to efficiently care for patients comes with time and hard work, but here are five tips that will make your first few years as a nurse practitioner or physician assistant easier.

Derm Dx

Julee Waldrop, DNP, PNP, FNP Axing unnecessary tests and procedures to cut health-care costs An adolescent patient received a battery of unnecessary tests, including chest x-rays, when he visited the emergency department for viral respiratory symptoms. When will it stop?

Interact with your peers by viewing the images and offering your diagnosis and comments.

ClinicalAdvisor.com/DermDx0512A

Sharon M. O’Brien, MPAS, PA-C Exploding-head syndrome or SSRI withdrawal?

A patient visits the sleep clinic complaining of being awakened by a noise that sounded like a bomb.

An asymptomatic eruption on the back An obese but otherwise well patient presents with an asymptomatic eruption between her shoulder blades.

MAKING CONTACT

Follow us on Twitter @ClinicalAdvisor

Robyn Carlisle, MSN, CNM, WHNP The line between casual and unprofessional is easy to overstep Like bedside manner and compassion, professionalism is a skill that is difficult to teach to medical students—and may be even more difficult to learn.

Like us on Facebook facebook.com/TheClinicalAdvisor

14 THE CLINICAL ADVISOR • MAY 2011 • www.clinicaladvisor.com

Visit us on the web ClinicalAdvisor.com

Go mobile with us mobile.ClinicalAdvisor.com

While there are many diabetes complications,

PAINFUL DPN IS ONE THEY CAN’T IGNORE Help manage your patients’ painful Diabetic Peripheral Neuropathy with LYRICA

ONLY LYRICA IS RECOMMENDED AS LEVEL A by AAN evidence-based guideline for the treatment of painful diabetic neuropathy (PDN)1

“If clinically appropriate, pregabalin should be offered for the treatment of PDN (Level A).”1 The medical organizations that developed this guideline (the AAN, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation) recognize that specific care decisions are the prerogative of the patient and physician caring for the patient, based on all of the circumstances involved.

For full guideline, visit www.aan.com/guidelines.

Level A=Established as effective, based on at least 2 Class I studies.

Class I level evidence includes a randomized, controlled clinical trial of the intervention of interest with masked or objective outcome assessment, in a representative population, and other specified criteria.

AAN=American Academy of Neurology.

LYRICA is indicated for the management of neuropathic pain associated with Diabetic Peripheral Neuropathy, management of Postherpetic Neuralgia, as adjunctive therapy for adult patients with Partial Onset Seizures, and management of Fibromyalgia.

PBP01859A/291945-01

© 2011 Pfizer Inc.

Selected safety information: LYRICA is contraindicated in patients with known hypersensitivity to pregabalin or any of its other components. There have been postmarketing reports of hypersensitivity in patients shortly after initiation of treatment with LYRICA. Adverse reactions included skin redness, blisters, hives, rash, dyspnea, and wheezing. Discontinue LYRICA immediately in patients with these symptoms.

There have been postmarketing reports of angioedema in patients during initial and chronic treatment with LYRICA. Specific symptoms included swelling of the face, mouth (tongue, lips, and gums), and neck (throat and larynx). There were reports of lifethreatening angioedema with respiratory compromise requiring emergency treatment. Discontinue LYRICA immediately in patients with these symptoms.

Antiepileptic drugs (AEDs) including LYRICA increase the risk of suicidal thoughts or behavior in patients taking AEDs for any indication. Monitor patients treated with any AED for any indication for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Pooled analyses showed clinical trial patients taking an AED had approximately twice the risk of suicidal thoughts or behavior than placebotreated patients, and estimated the incidence rate of suicidal behavior or ideation was approximately one patient for every 530 patients treated with an AED. The most common adverse reactions across all LYRICA All rights reserved.

clinical trials are dizziness, somnolence, dry mouth, edema, blurred vision, weight gain, constipation, euphoric mood, balance disorder, increased appetite, and thinking abnormal (primarily difficulty with concentration/attention).

Inform patients taking LYRICA that dizziness and somnolence may impair their ability to perform potentially hazardous tasks such as driving or operating complex machinery until they have sufficient experience with LYRICA to determine its effect on cognitive and motor function.

Higher frequency of weight gain and edema was observed in patients taking both LYRICA and thiazolidinedione antidiabetic drugs. Exercise caution when coadministering these drugs. Patients who are taking other drugs associated with angioedema such as angiotensin-converting enzyme inhibitors (ACE inhibitors) may be at increased risk of developing angioedema. Exercise caution when using LYRICA in patients who have had a previous episode of angioedema.

For Full Prescribing Information and Medication Guide, please visit www.LyricaHCP.com.

Please see the Brief Summary of Prescribing Information on adjacent pages.

Reference: 1. Bril V, England JD, Franklin GM, et al. Evidence-based guideline: treatment of painful diabetic neuropathy. Report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. Neurology. 2011;76:1758-1765.

September 2011

LYRICA® (pregabalin) CAPSULES BRIEF SUMMARY: For full prescribing information, see package insert.

INDICATION AND USAGE LYRICA is indicated for: • Management of neuropathic pain associated with diabetic peripheral neuropathy DOSAGE AND ADMINISTRATION LYRICA is given orally with or without food. When discontinuing LYRICA, taper gradually over a minimum of 1 week.

Neuropathic pain associated with diabetic peripheral neuropathy: • Administer in 3 divided doses per day • Begin dosing at 150 mg/day • May be increased to a maximum of 300 mg/day within 1 week • Dose should be adjusted for patients with reduced renal function Patients with Renal Impairment In view of dose-dependent adverse reactions and since LYRICA is eliminated primarily by renal excretion, adjust the dose in patients with reduced renal function. Base the dose adjustment in patients with renal impairment on creatinine clearance (CLcr), as indicated in Table 1. To use this dosing table, an estimate of the patient’s CLcr in mL/min is needed. CLcr in mL/min may be estimated from serum creatinine (mg/dL) determination using the Cockcroft and Gault equation: [140 - age (years)] x weight (kg) CLCr =

(x 0.85 for female patients) 72 x serum creatinine (mg/dL) Next, refer to the Dosage and Administration section to determine the recommended total daily dose based on indication, for a patient with normal renal function (CLcr ≥60 mL/min). Then refer to Table 1 to determine the corresponding renal adjusted dose.

(For example: A patient initiating LYRICA therapy for postherpetic neuralgia with normal renal function (CLcr ≥60 mL/min), receives a total daily dose of 150 mg/day pregabalin. Therefore, a renal impaired patient with a CLcr of 50 mL/min would receive a total daily dose of 75 mg/day pregabalin administered in two or three divided doses.)

For patients undergoing hemodialysis, adjust the pregabalin daily dose based on renal function. In addition to the daily dose adjustment, administer a supplemental dose immediately following every 4-hour hemodialysis treatment (see Table 1).

Table 1. Pregabalin Dosage Adjustment Based on Renal Function Creatinine Clearance Total Pregabalin Daily Dose (CLcr) (mL/min) (mg/day)* ≥60 150 300 450 600 30–60

75

15–30 <15

Dose Regimen BID or TID

150

225

300

BID or TID

25–50

75

100–150

150

QD or BID

25

25–50

50–75

75

QD

Supplementary dosage following hemodialysis (mg)† Patients on the 25 mg QD regimen: take one supplemental dose of 25 mg or 50 mg Patients on the 25–50 mg QD regimen: take one supplemental dose of 50 mg or 75 mg Patients on the 50–75 mg QD regimen: take one supplemental dose of 75 mg or 100 mg Patients on the 75 mg QD regimen: take one supplemental dose of 100 mg or 150 mg TID = Three divided doses; BID = Two divided doses; QD = Single daily dose. *Total daily dose (mg/day) should be divided as indicated by dose regimen to provide mg/dose. †Supplementary dose is a single additional dose.

CONTRAINDICATIONS LYRICA is contraindicated in patients with known hypersensitivity to pregabalin or any of its components. Angioedema and hypersensitivity reactions have occurred in patients receiving pregabalin therapy.

WARNINGS AND PRECAUTIONS Angioedema There have been postmarketing reports of angioedema in patients during initial and chronic treatment with LYRICA. Specific symptoms included swelling of the face, mouth (tongue, lips, and gums), and neck (throat and larynx). There were reports of life-threatening angioedema with respiratory compromise requiring emergency treatment.

Discontinue LYRICA immediately in patients with these symptoms. Exercise caution when prescribing LYRICA to patients who have had a previous episode of angioedema. In addition, patients who are taking other drugs associated with angioedema (e.g., angiotensin converting enzyme inhibitors [ACE-inhibitors]) may be at increased risk of developing angioedema. Hypersensitivity There have been postmarketing reports of hypersensitivity in patients shortly after initiation of treatment with LYRICA. Adverse reactions included skin redness, blisters, hives, rash, dyspnea, and wheezing.

Discontinue LYRICA immediately in patients with these symptoms. Withdrawal of Antiepileptic Drugs (AEDs) As with all AEDs, withdraw LYRICA gradually to minimize the potential of increased seizure frequency in patients with seizure disorders. If LYRICA is discontinued, taper the drug gradually over a minimum of 1 week. Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including LYRICA, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Monitor patients treated with any AED for any indication for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI: 1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. Table 2 shows absolute and relative risk by indication for all evaluated AEDs. Table 2 Risk by indication for antiepileptic drugs in the pooled analysis Indication Placebo Patients Drug Patients Relative Risk: Risk Difference: with Events Per with Events Per Incidence of Events Additional Drug Patients 1000 Patients 1000 Patients in Drug Patients/Incidence with Events Per in Placebo Patients 1000 Patients Epilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9 The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.

Anyone considering prescribing LYRICA or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. Inform patients, their caregivers, and families that LYRICA and other AEDs increase the risk of suicidal thoughts and behavior and advise them of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Report behaviors of concern immediately to healthcare providers. Peripheral Edema LYRICA treatment may cause peripheral edema. In short-term trials of patients

without clinically significant heart or peripheral vascular disease, there was no apparent association between peripheral edema and cardiovascular complications such as hypertension or congestive heart failure. Peripheral edema was not associated with laboratory changes suggestive of deterioration in renal or hepatic function. In controlled clinical trials the incidence of peripheral edema was 6% in the LYRICA group compared with 2% in the placebo group. In controlled clinical trials, 0.5% of LYRICA patients and 0.2% placebo patients withdrew due to peripheral edema. Higher frequencies of weight gain and peripheral edema were observed in patients taking both LYRICA and a thiazolidinedione antidiabetic agent compared to patients taking either drug alone. The majority of patients using thiazolidinedione antidiabetic agents in the overall safety database were participants in studies of pain associated with diabetic peripheral neuropathy. In this population, peripheral edema was reported in 3% (2/60) of patients who were using thiazolidinedione antidiabetic agents only, 8% (69/859) of patients who were treated with LYRICA only, and 19% (23/120) of patients who were on both LYRICA and thiazolidinedione antidiabetic agents. Similarly, weight gain was reported in 0% (0/60) of patients on thiazolidinediones only; 4% (35/859) of patients on LYRICA only; and 7.5% (9/120) of patients on both drugs. As the thiazolidinedione class of antidiabetic drugs can cause weight gain and/or fluid retention, possibly exacerbating or leading to heart failure, exercise caution when co-administering LYRICA and these agents. Because there are limited data on congestive heart failure patients with New York Heart Association (NYHA) Class III or IV cardiac status, exercise caution when using LYRICA in these patients. Dizziness and Somnolence LYRICA may cause dizziness and somnolence. Inform patients that LYRICA-related dizziness and somnolence may impair their ability to perform tasks such as driving or operating machinery. In the LYRICA controlled trials, dizziness was experienced by 31% of LYRICAtreated patients compared to 9% of placebo-treated patients; somnolence was experienced by 22% of LYRICA-treated patients compared to 7% of placebo-treated patients. Dizziness and somnolence generally began shortly after the initiation of LYRICA therapy and occurred more frequently at higher doses. Dizziness and somnolence were the adverse reactions most frequently leading to withdrawal (4% each) from controlled studies. In LYRICA-treated patients reporting these adverse reactions in short-term, controlled studies, dizziness persisted until the last dose in 30% and somnolence persisted until the last dose in 42% of patients. Weight Gain LYRICA treatment may cause weight gain. In LYRICA controlled clinical trials of up to 14 weeks, a gain of 7% or more over baseline weight was observed in 9% of LYRICAtreated patients and 2% of placebo-treated patients. Few patients treated with LYRICA (0.3%) withdrew from controlled trials due to weight gain. LYRICA associated weight gain was related to dose and duration of exposure, but did not appear to be associated with baseline BMI, gender, or age. Weight gain was not limited to patients with edema [see Warnings and Precautions, Peripheral Edema]. Although weight gain was not associated with clinically important changes in blood pressure in short-term controlled studies, the long-term cardiovascular effects of LYRICA-associated weight gain are unknown. Among diabetic patients, LYRICA-treated patients gained an average of 1.6 kg (range: -16 to 16 kg), compared to an average 0.3 kg (range: -10 to 9 kg) weight gain in placebo patients. In a cohort of 333 diabetic patients who received LYRICA for at least 2 years, the average weight gain was 5.2 kg. While the effects of LYRICAassociated weight gain on glycemic control have not been systematically assessed, in controlled and longer-term open label clinical trials with diabetic patients, LYRICA treatment did not appear to be associated with loss of glycemic control (as measured by HbA1C). Abrupt or Rapid Discontinuation Following abrupt or rapid discontinuation of LYRICA, some patients reported symptoms including insomnia, nausea, headache, and diarrhea. Taper LYRICA gradually over a minimum of 1 week rather than discontinuing the drug abruptly. Tumorigenic Potential In standard preclinical in vivo lifetime carcinogenicity studies of LYRICA, an unexpectedly high incidence of hemangiosarcoma was identified in two different strains of mice [see Nonclinical Toxicology, Carcinogenesis, Mutagenesis, Impairment of Fertility]. The clinical significance of this finding is unknown. Clinical experience during LYRICA’s premarketing development provides no direct means to assess its potential for inducing tumors in humans. In clinical studies across various patient populations, comprising 6396 patient-years of exposure in patients >12 years of age, new or worsening-preexisting tumors were reported in 57 patients. Without knowledge of the background incidence and recurrence in similar populations not treated with LYRICA, it is impossible to know whether the incidence seen in these cohorts is or is not affected by treatment. Ophthalmological Effects In controlled studies, a higher proportion of patients treated with LYRICA reported blurred vision (7%) than did patients treated with placebo (2%), which resolved in a majority of cases with continued dosing. Less than 1% of patients discontinued LYRICA treatment due to vision-related events (primarily blurred vision).

Prospectively planned ophthalmologic testing, including visual acuity testing, formal visual field testing and dilated funduscopic examination, was performed in over 3600 patients. In these patients, visual acuity was reduced in 7% of patients treated with LYRICA, and 5% of placebo-treated patients. Visual field changes were detected in 13% of LYRICAtreated, and 12% of placebo-treated patients. Funduscopic changes were observed in 2% of LYRICA-treated and 2% of placebo-treated patients. Although the clinical significance of the ophthalmologic findings is unknown, inform patients to notify their physician if changes in vision occur. If visual disturbance persists, consider further assessment. Consider more frequent assessment for patients who are already routinely monitored for ocular conditions. Creatine Kinase Elevations LYRICA treatment was associated with creatine kinase elevations. Mean changes in creatine kinase from baseline to the maximum value were 60 U/L for LYRICA-treated patients and 28 U/L for the placebo patients. In all controlled trials across multiple patient populations, 1.5% of patients on LYRICA and 0.7% of placebo patients had a value of creatine kinase at least three times the upper limit of normal. Three LYRICA-treated subjects had events reported as rhabdomyolysis in premarketing clinical trials. The relationship between these myopathy events and LYRICA is not completely understood because the cases had documented factors that may have caused or contributed to these events.

Instruct patients to promptly report unexplained muscle pain, tenderness, or weakness, particularly if these muscle symptoms are accompanied by malaise or fever. Discontinue treatment with LYRICA if myopathy is diagnosed or suspected or if markedly elevated creatine kinase levels occur. Decreased Platelet Count LYRICA treatment was associated with a decrease in platelet count. LYRICA-treated subjects experienced a mean maximal decrease in platelet count of 20 x 10 3/µL, compared to 11 x 10 3/µL in placebo patients. In the overall database of controlled trials, 2% of placebo patients and 3% of LYRICA patients experienced a potentially clinically significant decrease in platelets, defined as 20% below baseline value and <150 x 10 3/µL. A single LYRICA treated subject developed severe thrombocytopenia with a platelet count less than 20 x 103/µL. In randomized controlled trials, LYRICA was not associated with an increase in bleeding-related adverse reactions. PR Interval Prolongation LYRICA treatment was associated with PR interval prolongation. In analyses of clinical trial ECG data, the mean PR interval increase was 3–6 msec at LYRICA doses ≥300 mg/day. This mean change difference was not associated with an increased risk of PR increase ≥25% from baseline, an increased percentage of subjects with on-treatment PR >200 msec, or an increased risk of adverse reactions of second or third degree AV block. Subgroup analyses did not identify an increased risk of PR prolongation in patients with baseline PR prolongation or in patients taking other PR prolonging medications. However, these analyses cannot be considered definitive because of the limited number of patients in these categories.

ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In all controlled and uncontrolled trials across various patient populations during the premarketing development of LYRICA, more than 10,000 patients have received LYRICA. Approximately 5000 patients were treated for 6 months or more, over 3100 patients were treated for 1 year or longer, and over 1400 patients were treated for at least 2 years.

Adverse Reactions Most Commonly Leading to Discontinuation in All Premarketing Controlled Clinical Studies In premarketing controlled trials of all populations combined, 14% of patients treated with LYRICA and 7% of patients treated with placebo discontinued prematurely due to adverse reactions. In the LYRICA treatment group, the adverse reactions most frequently leading to discontinuation were dizziness (4%) and somnolence (3%). In the placebo group, 1% of patients withdrew due to dizziness and <1% withdrew due to somnolence. Other adverse reactions that led to discontinuation from controlled trials more frequently in the LYRICA group compared to the placebo group were ataxia, confusion, asthenia, thinking abnormal, blurred vision, incoordination, and peripheral edema (1% each).

Most Common Adverse Reactions in All Premarketing Controlled Clinical Studies In premarketing controlled trials of all patient populations combined, dizziness, somnolence, dry mouth, edema, blurred vision, weight gain, and “thinking abnormal” (primarily difficulty with concentration/attention) were more commonly reported by subjects treated with LYRICA than by subjects treated with placebo (≥5% and twice the rate of that seen in placebo).

Controlled Studies with Neuropathic Pain Associated with Diabetic Peripheral Neuropathy Adverse Reactions Leading to Discontinuation In clinical trials in patients with neuropathic pain associated with diabetic peripheral neuropathy, 9% of patients treated with LYRICA and 4% of patients treated with placebo discontinued prematurely due to adverse reactions. In the LYRICA treatment group, the most common reasons for discontinuation due to adverse reactions were dizziness (3%) and somnolence (2%). In comparison, <1% of placebo patients withdrew due to dizziness and somnolence. Other reasons for discontinuation from the trials, occurring with greater frequency in the LYRICA group than in the placebo group, were asthenia, confusion, and peripheral edema. Each of these events led to withdrawal in approximately 1% of patients.

Most Common Adverse Reactions Table 3 lists all adverse reactions, regardless of causality, occurring in ≥1% of patients with neuropathic pain associated with diabetic neuropathy in the combined LYRICA group for which the incidence was greater in this combined LYRICA group than in the placebo group. A majority of pregabalin-treated patients in clinical studies had adverse reactions with a maximum intensity of “mild” or “moderate”.

Table 3 Treatment-emergent adverse reaction incidence in controlled trials in Neuropathic Pain Associated with Diabetic Peripheral Neuropathy (Events in at least 1% of all LYRICA-treated patients and at least numerically more in all LYRICA than in the placebo group) 75 mg/d 150 mg/d 300 mg/d 600 mg/d All PGB* Placebo Body System [N=77] [N=212] [N=321] [N=369] [N=979] [N=459] - Preferred term % % % % % % Body as a whole Asthenia 4 2 4 7 5 2 Accidental injury 5 2 2 6 4 3 Back pain 0 2 1 2 2 0 Chest pain 4 1 1 2 2 1 Face edema 0 1 1 2 1 0 Digestive system Dry mouth 3 2 5 7 5 1 Constipation 0 2 4 6 4 2 Flatulence 3 0 2 3 2 1 Metabolic and nutritional disorders Peripheral edema 4 6 9 12 9 2 Weight gain 0 4 4 6 4 0 Edema 0 2 4 2 2 0 Hypoglycemia 1 3 2 1 2 1 Nervous system Dizziness 8 9 23 29 21 5 Somnolence 4 6 13 16 12 3 Neuropathy 9 2 2 5 4 3 Ataxia 6 1 2 4 3 1 Vertigo 1 2 2 4 3 1 Confusion 0 1 2 3 2 1 Euphoria 0 0 3 2 2 0 Incoordination 1 0 2 2 2 0 1 0 1 3 2 0 Thinking abnormal† Tremor 1 1 1 2 1 0 Abnormal gait 1 0 1 3 1 0 Amnesia 3 1 0 2 1 0 Nervousness 0 1 1 1 1 0 Respiratory system Dyspnea 3 0 2 2 2 1 Special senses 3 1 3 6 4 2 Blurry vision‡ Abnormal vision 1 0 1 1 1 0 *PGB: pregabalin † Thinking abnormal primarily consists of events related to difficulty with concentration/attention but also includes events related to cognition and language problems and slowed thinking. ‡ Investigator term; summary level term is amblyopia.

Other Adverse Reactions Observed During the Clinical Studies of LYRICA Following is a list of treatment-emergent adverse reactions reported by patients treated with LYRICA during all clinical trials. The listing does not include those events already listed in the previous tables or elsewhere in labeling, those events for which a drug cause was remote, those events which were so general as to be uninformative, and those events reported only once which did not have a substantial probability of being acutely life-threatening. Events are categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse reactions are those occurring on one or more occasions in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions are those occurring in fewer than 1/1000 patients. Events of major clinical importance are described in the Warnings and Precautions section.

Body as a Whole – Frequent: Abdominal pain, Allergic reaction, Fever; Infrequent: Abscess, Cellulitis, Chills, Malaise, Neck rigidity, Overdose, Pelvic pain, Photosensitivity reaction; Rare: Anaphylactoid reaction, Ascites, Granuloma, Hangover effect, Intentional Injury, Retroperitoneal Fibrosis, Shock. Cardiovascular System – Infrequent: Deep thrombophlebitis, Heart failure, Hypotension, Postural hypotension, Retinal vascular disorder, Syncope; Rare: ST Depressed, Ventricular Fibrillation.

Digestive System – Frequent: Gastroenteritis, Increased appetite; Infrequent: Cholecystitis, Cholelithiasis, Colitis, Dysphagia, Esophagitis, Gastritis, Gastrointestinal hemorrhage, Melena, Mouth ulceration, Pancreatitis, Rectal hemorrhage, Tongue edema; Rare: Aphthous stomatitis, Esophageal Ulcer, Periodontal abscess. Hemic and Lymphatic System – Frequent: Ecchymosis; Infrequent: Anemia, Eosinophilia, Hypochromic anemia, Leukocytosis, Leukopenia, Lymphadenopathy, Thrombocytopenia; Rare: Myelofibrosis, Polycythemia, Prothrombin decreased, Purpura, Thrombocythemia. Metabolic and Nutritional Disorders – Rare: Glucose Tolerance Decreased, Urate Crystalluria. Musculoskeletal System – Frequent: Arthralgia, Leg cramps, Myalgia, Myasthenia; Infrequent: Arthrosis; Rare: Chondrodystrophy, Generalized Spasm. Nervous System – Frequent: Anxiety, Depersonalization, Hypertonia, Hypesthesia, Libido decreased, Nystagmus, Paresthesia, Stupor, Twitching; Infrequent: Abnormal dreams, Agitation, Apathy, Aphasia, Circumoral paresthesia, Dysarthria, Hallucinations, Hostility, Hyperalgesia, Hyperesthesia, Hyperkinesia, Hypokinesia, Hypotonia, Libido increased, Myoclonus, Neuralgia; Rare: Addiction, Cerebellar syndrome, Cogwheel rigidity, Coma, Delirium, Delusions, Dysautonomia, Dyskinesia, Dystonia, Encephalopathy, Extrapyramidal syndrome, Guillain-Barré syndrome, Hypalgesia, Intracranial hypertension, Manic reaction, Paranoid reaction, Peripheral neuritis, Personality disorder, Psychotic depression, Schizophrenic reaction, Sleep disorder, Torticollis, Trismus. Respiratory System – Rare: Apnea, Atelectasis, Bronchiolitis, Hiccup, Laryngismus, Lung edema, Lung fibrosis, Yawn. Skin and Appendages – Frequent: Pruritus; Infrequent: Alopecia, Dry skin, Eczema, Hirsutism, Skin ulcer, Urticaria, Vesiculobullous rash; Rare: Angioedema, Exfoliative dermatitis, Lichenoid dermatitis, Melanosis, Nail Disorder, Petechial rash, Purpuric rash, Pustular rash, Skin atrophy, Skin necrosis, Skin nodule, Stevens-Johnson syndrome, Subcutaneous nodule. Special senses – Frequent: Conjunctivitis, Diplopia, Otitis media, Tinnitus; Infrequent: Abnormality of accommodation, Blepharitis, Dry eyes, Eye hemorrhage, Hyperacusis, Photophobia, Retinal edema, Taste loss, Taste perversion; Rare: Anisocoria, Blindness, Corneal ulcer, Exophthalmos, Extraocular palsy, Iritis, Keratitis, Keratoconjunctivitis, Miosis, Mydriasis, Night blindness, Ophthalmoplegia, Optic atrophy, Papilledema, Parosmia, Ptosis, Uveitis. Urogenital System – Frequent: Anorgasmia, Impotence, Urinary frequency, Urinary incontinence; Infrequent: Abnormal ejaculation, Albuminuria, Amenorrhea, Dysmenorrhea, Dysuria, Hematuria, Kidney calculus, Leukorrhea, Menorrhagia, Metrorrhagia, Nephritis, Oliguria, Urinary retention, Urine abnormality; Rare: Acute kidney failure, Balanitis, Bladder Neoplasm, Cervicitis, Dyspareunia, Epididymitis, Female lactation, Glomerulitis, Ovarian disorder, Pyelonephritis.

Comparison of Gender and Race The overall adverse event profile of pregabalin was similar between women and men.

There are insufficient data to support a statement regarding the distribution of adverse experience reports by race.

Post-marketing Experience The following adverse reactions have been identified during postapproval use of LYRICA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Nervous System Disorders – Headache.

Gastrointestinal Disorders – Nausea, Diarrhea. Reproductive System and Breast Disorders – Gynecomastia, Breast Enlargement.

DRUG INTERACTIONS Since LYRICA is predominantly excreted unchanged in the urine, undergoes negligible metabolism in humans (<2% of a dose recovered in urine as metabolites), and does not bind to plasma proteins, its pharmacokinetics are unlikely to be affected by other agents through metabolic interactions or protein binding displacement. In vitro and in vivo studies showed that LYRICA is unlikely to be involved in significant pharmacokinetic drug interactions. Specifically, there are no pharmacokinetic interactions between pregabalin and the following antiepileptic drugs: carbamazepine, valproic acid, lamotrigine, phenytoin, phenobarbital, and topiramate. Important pharmacokinetic interactions would also not be expected to occur between LYRICA and commonly used antiepileptic drugs.

Pharmacodynamics Multiple oral doses of LYRICA were co-administered with oxycodone, lorazepam, or ethanol. Although no pharmacokinetic interactions were seen, additive effects on cognitive and gross motor functioning were seen when LYRICA was co-administered with these drugs. No clinically important effects on respiration were seen.

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C. Increased incidences of fetal structural abnormalities and other manifestations of developmental toxicity, including lethality, growth retardation, and nervous and reproductive system functional impairment, were observed in the offspring of rats and rabbits given pregabalin during pregnancy, at doses that produced plasma pregabalin exposures (AUC) ≥5 times human exposure at the maximum recommended dose (MRD) of 600 mg/day.

When pregnant rats were given pregabalin (500, 1250, or 2500 mg/kg) orally throughout the period of organogenesis, incidences of specific skull alterations attributed to abnormally advanced ossification (premature fusion of the jugal and nasal sutures) were increased at ≥1250 mg/kg, and incidences of skeletal variations and retarded ossification were increased at all doses. Fetal body weights were decreased at the highest dose. The low dose in this study was associated with a plasma exposure (AUC) approximately 17 times human exposure at the MRD of 600 mg/day. A no-effect dose for

rat embryo-fetal developmental toxicity was not established. When pregnant rabbits were given LYRICA (250, 500, or 1250 mg/kg) orally throughout the period of organogenesis, decreased fetal body weight and increased incidences of skeletal malformations, visceral variations, and retarded ossification were observed at the highest dose. The no-effect dose for developmental toxicity in rabbits (500 mg/kg) was associated with a plasma exposure approximately 16 times human exposure at the MRD. In a study in which female rats were dosed with LYRICA (50, 100, 250, 1250, or 2500 mg/kg) throughout gestation and lactation, offspring growth was reduced at ≥100 mg/kg and offspring survival was decreased at ≥250 mg/kg. The effect on offspring survival was pronounced at doses ≥1250 mg/kg, with 100% mortality in high-dose litters. When offspring were tested as adults, neurobehavioral abnormalities (decreased auditory startle responding) were observed at ≥250 mg/kg and reproductive impairment (decreased fertility and litter size) was seen at 1250 mg/kg. The no-effect dose for pre- and postnatal developmental toxicity in rats (50 mg/kg) produced a plasma exposure approximately 2 times human exposure at the MRD. There are no adequate and well-controlled studies in pregnant women. Use LYRICA during pregnancy only if the potential benefit justifies the potential risk to the fetus. To provide information regarding the effects of in utero exposure to LYRICA, physicians are advised to recommend that pregnant patients taking LYRICA enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www. aedpregnancyregistry.org/. Labor and Delivery The effects of LYRICA on labor and delivery in pregnant women are unknown. In the prenatal-postnatal study in rats, pregabalin prolonged gestation and induced dystocia at exposures ≥50 times the mean human exposure (AUC (0–24) of 123 µg•hr/mL) at the maximum recommended clinical dose of 600 mg/day. Nursing Mothers It is not known if pregabalin is excreted in human milk; it is, however, present in the milk of rats. Because many drugs are excreted in human milk, and because of the potential for tumorigenicity shown for pregabalin in animal studies, decide whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and efficacy of pregabalin in pediatric patients have not been established. In studies in which pregabalin (50 to 500 mg/kg) was orally administered to young rats from early in the postnatal period (Postnatal Day 7) through sexual maturity, neurobehavioral abnormalities (deficits in learning and memory, altered locomotor activity, decreased auditory startle responding and habituation) and reproductive impairment (delayed sexual maturation and decreased fertility in males and females) were observed at doses ≥50 mg/kg. The neurobehavioral changes of acoustic startle persisted at ≥250 mg/kg and locomotor activity and water maze performance at ≥500 mg/kg in animals tested after cessation of dosing and, thus, were considered to represent long-term effects. The low effect dose for developmental neurotoxicity and reproductive impairment in juvenile rats (50 mg/kg) was associated with a plasma pregabalin exposure (AUC) approximately equal to human exposure at the maximum recommended dose of 600 mg/day. A no-effect dose was not established. Geriatric Use In controlled clinical studies of LYRICA in neuropathic pain associated with diabetic peripheral neuropathy, 246 patients were 65 to 74 years of age, and 73 patients were 75 years of age or older. In controlled clinical studies of LYRICA in neuropathic pain associated with postherpetic neuralgia, 282 patients were 65 to 74 years of age, and 379 patients were 75 years of age or older. No overall differences in safety and efficacy were observed between these patients and younger patients. In controlled clinical studies of LYRICA in fibromyalgia, 106 patients were 65 years of age or older. Although the adverse reaction profile was similar between the two age groups, the following neurological adverse reactions were more frequent in patients 65 years of age or older: dizziness, vision blurred, balance disorder, tremor, confusional state, coordination abnormal, and lethargy.

LYRICA is known to be substantially excreted by the kidney, and the risk of toxic reactions to LYRICA may be greater in patients with impaired renal function. Because LYRICA is eliminated primarily by renal excretion, adjust the dose for elderly patients with renal impairment.

DRUG ABUSE AND DEPENDENCE Controlled Substance LYRICA is a Schedule V controlled substance. LYRICA is not known to be active at receptor sites associated with drugs of abuse. As with any CNS active drug, carefully evaluate patients for history of drug abuse and observe them for signs of LYRICA misuse or abuse (e.g., development of tolerance, dose escalation, drug-seeking behavior).

Abuse In a study of recreational users (N=15) of sedative/hypnotic drugs, including alcohol, LYRICA (450 mg, single dose) received subjective ratings of “good drug effect,” “high” and “liking” to a degree that was similar to diazepam (30 mg, single dose). In controlled clinical studies in over 5500 patients, 4% of LYRICA-treated patients and 1% of placebo-treated patients overall reported euphoria as an adverse reaction, though in some patient populations studied, this reporting rate was higher and ranged from 1 to 12%. Dependence In clinical studies, following abrupt or rapid discontinuation of LYRICA, some patients reported symptoms including insomnia, nausea, headache or diarrhea [see Warnings and Precautions, Abrupt or Rapid Discontinuation], suggestive of physical dependence.

OVERDOSAGE Signs, Symptoms and Laboratory Findings of Acute Overdosage in Humans There is limited experience with overdose of LYRICA. The highest reported accidental overdose of LYRICA during the clinical development program was 8000 mg, and there were no notable clinical consequences. Treatment or Management of Overdose There is no specific antidote for overdose with LYRICA. If indicated, elimination of unabsorbed drug may be attempted by emesis or gastric lavage; observe usual precautions to maintain the airway. General supportive care of the patient is indicated including monitoring of vital signs and observation of the clinical status of the patient. Contact a Certified Poison Control Center for up-to-date information on the management of overdose with LYRICA. Although hemodialysis has not been performed in the few known cases of overdose, it may be indicated by the patient’s clinical state or in patients with significant renal impairment.

Standard hemodialysis procedures result in significant clearance of pregabalin (approximately 50% in 4 hours).

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis A dose-dependent increase in the incidence of malignant vascular tumors (hemangiosarcomas) was observed in two strains of mice (B6C3F1 and CD-1) given pregabalin (200, 1000, or 5000 mg/kg) in the diet for two years. Plasma pregabalin exposure (AUC) in mice receiving the lowest dose that increased hemangiosarcomas was approximately equal to the human exposure at the maximum recommended dose (MRD) of 600 mg/day. A no-effect dose for induction of hemangiosarcomas in mice was not established. No evidence of carcinogenicity was seen in two studies in Wistar rats following dietary administration of pregabalin for two years at doses (50, 150, or 450 mg/kg in males and 100, 300, or 900 mg/kg in females) that were associated with plasma exposures in males and females up to approximately 14 and 24 times, respectively, human exposure at the MRD. Mutagenesis Pregabalin was not mutagenic in bacteria or in mammalian cells in vitro, was not clastogenic in mammalian systems in vitro and in vivo, and did not induce unscheduled DNA synthesis in mouse or rat hepatocytes. Impairment of Fertility In fertility studies in which male rats were orally administered pregabalin (50 to 2500 mg/kg) prior to and during mating with untreated females, a number of adverse reproductive and developmental effects were observed. These included decreased sperm counts and sperm motility, increased sperm abnormalities, reduced fertility, increased preimplantation embryo loss, decreased litter size, decreased fetal body weights, and an increased incidence of fetal abnormalities. Effects on sperm and fertility parameters were reversible in studies of this duration (3–4 months). The no-effect dose for male reproductive toxicity in these studies (100 mg/kg) was associated with a plasma pregabalin exposure (AUC) approximately 3 times human exposure at the maximum recommended dose (MRD) of 600 mg/day. In addition, adverse reactions on reproductive organ (testes, epididymides) histopathology were observed in male rats exposed to pregabalin (500 to 1250 mg/kg) in general toxicology studies of four weeks or greater duration. The no-effect dose for male reproductive organ histopathology in rats (250 mg/kg) was associated with a plasma exposure approximately 8 times human exposure at the MRD. In a fertility study in which female rats were given pregabalin (500, 1250, or 2500 mg/kg) orally prior to and during mating and early gestation, disrupted estrous cyclicity and an increased number of days to mating were seen at all doses, and embryolethality occurred at the highest dose. The low dose in this study produced a plasma exposure approximately 9 times that in humans receiving the MRD. A no-effect dose for female reproductive toxicity in rats was not established. Human Data In a double-blind, placebo-controlled clinical trial to assess the effect of pregabalin on sperm motility, 30 healthy male subjects were exposed to pregabalin at a dose of 600 mg/day. After 3 months of treatment (one complete sperm cycle), the difference between placebo- and pregabalintreated subjects in mean percent sperm with normal motility was <4% and neither group had a mean change from baseline of more than 2%. Effects on other male reproductive parameters in humans have not been adequately studied.

Animal Toxicology and/or Pharmacology Dermatopathy Skin lesions ranging from erythema to necrosis were seen in repeated-dose toxicology studies in both rats and monkeys. The etiology of these skin lesions is unknown. At the maximum recommended human dose (MRD) of 600 mg/day, there is a 2-fold safety margin for the dermatological lesions. The more severe dermatopathies involving necrosis were associated with pregabalin exposures (as expressed by plasma AUCs) of approximately 3 to 8 times those achieved in humans given the MRD. No increase in incidence of skin lesions was observed in clinical studies. Ocular Lesions Ocular lesions (characterized by retinal atrophy [including loss of photoreceptor cells] and/or corneal inflammation/mineralization) were observed in two lifetime carcinogenicity studies in Wistar rats. These findings were observed at plasma pregabalin exposures (AUC) ≥2 times those achieved in humans given the maximum recommended dose of 600 mg/day. A no-effect dose for ocular lesions was not established. Similar lesions were not observed in lifetime carcinogenicity studies in two strains of mice or in monkeys treated for 1 year.

LAB-0294-21.0 June 2011

PBP01873/291898-01

© 2011 Pfizer Inc.

All rights reserved.

Newsline M AY 2 0 12

“Choose wisely” when ordering specific tests page 20

Patients may need help in identifying nuts page 22

Guide to using antibiotics for sinus infections page 22

© ISTOCKPHOTO.COM / DAVID SUCSY

Aspirin appears to keep cancer at bay

A TRIO OF studies adds support to earlier fi ndings that aspirin reduces cancer risk and, in some cases, metastasis.

Previous work by Peter M. Rothwell, FMedSci, who led all three of the current studies (two published online ahead of print

by The Lancet and one published online ahead of print by The Lancet Oncology), established that daily aspirin reduces the longterm risk of death from cancer.

One of the new Lancet studies clarified this effect by demonstrating that in 34 trials of low-dose aspirin for primary prevention of vascular events, involving 69,224 participants, persons allocated to aspirin had a risk of cancer death 15% lower than that of controls. The subset of patients who had been on aspirin therapy for at least five years was 27% less likely than the control group to die from cancer.

Daily aspirin has been shown to reduce the risk of death from cancer.

The same analysis revealed that in six trials of daily low-dose aspirin for primary prevention, using aspirin for at least three years reduced cancer incidence by 24% in women and by 23% in men, compared with controls.

In the other Lancet study, Rothwell’s team collected new data on the metastasis of cancers that had been diagnosed during all five large randomized trials in the United Kingdom evaluating daily aspirin (>75 mg/day) vs. control for the prevention of vascular events. During a mean follow-up of 6.5 years, people who had been allocated to aspirin therapy had a 36% lower risk of cancer with distant metastasis, a 46% lower risk of adenocarcinoma (such common solid cancers as colon, lung, and prostate cancers), and an 18% lower risk of such other solid cancers as bladder and kidney cancers.

The study also showed aspirin reduced risk of adenocarcinoma with metastasis at initial diagnosis by 31% and the risk of metastasis on follow-up in patients without initial metastasis by 55%—particularly in patients with colorectal cancer (by 74%) and in patients who remained on trial treatment up to or after diagnosis (by 69%).

The Lancet Oncology paper described a review of studies published from 1950 to 2011 that reported associations between aspirin use and risk or outcome of cancer. Observational studies showed a 38% reduced risk of colorectal cancer, which corresponded with the effect of daily aspirin use on 20-year risk of death from colorectal cancer from the randomized trials (42%). Similarly consistent reductions were seen in risks for esophageal, gastric, biliary, and breast cancers.

Distribution of BMI categories in adults age 20 and older Men were less likely than women to have a healthy weight, according to the Agency for Healthcare Research and Quality (AHRQ).

Source: Center for Financing, Access, and Cost Trends, AHRQ, Medical Expenditure Panel Survey, 2009

Male 3.0%

0.7%

Female 5.9%

2.2%

27.4%

26.3%

38.6%

24.0%

Underweight Healthy weight

42.6%

18 THE CLINICAL ADVISOR • MAY 2012 • www.ClinicalAdvisor.com

29.4%

Overweight Obese Extremely obese

Newsline SOME PATIENTS who are experiencing flulike symptoms— particularly elderly individuals— might actually be afflicted with babesiosis, a malaria-like disease caused by infection of red blood cells by a protozoan called Babesia.

This parasite is spread by ticks, with the peak transmission period being May through September.

Babesia are related to the parasites that cause malaria. Although infections can be asymptomatic, they can also cause mild fever, chills, and aches as well as other flulike symptoms. Severe complications, including multiorgan failure and death, mostly occur in the elderly, newborns, and persons who are immunocompromised or do not have a spleen.

A recent analysis of clinical babesiosis in persons aged 65 years and

older revealed that 985 Medicare patients had babesiosis in 2006 and 851 in 2007, but 1,223 had the disease in 2008 (Emerg Infect Dis. 2012;18:128-131).

The highest rates of babesiosis were found in persons aged 65 years and older who were living in New York, Connecticut, Rhode Island, or Massachusetts.

The infections appear to be on the rise in the District of Columbia, Maryland, and Virginia.

Ticks are also causing another problem in the Northeast: According to disease ecologist Richard S. Ostfeld, PhD, of the Cary Institute of Ecosystem Studies in Millbrook, N.Y., this region can expect a surge in Lyme disease this spring.

The problem began with a cyclical scarcity of acorns. A dearth of

© CDC / DR. MAE MELVIN

Tick-borne disease looks like the flu

Babesiosis is caused by the protozoan Babesia (red).

acorns reduces the population of white-footed mice, which are the preferred hosts of black-legged ticks. These ticks carry Borrelia burgdorferi, the bacterium that causes Lyme disease. With fewer mice off of which to feed, the ticks will be biting more humans, predicted Ostfeld.

NINE PHYSICIAN organizations have teamed up to identify specific tests or procedures commonly but not always practically used in their respective fields.

The A mer ican Board of Internal Medicine Foundation has brought together the American Academy of Family Physicians (AAFP), the American College of Physicians, the American College of Cardiolog y, the American College of Nuclear Card iolog y, the A mer ican Academy of Allergy, Asthma & Immunology, the American Gastroenterological Association,

Pap smears on women younger than age 21 are not necessary.

the American Society of Clinical Oncology, the American College of Radiology, and the American Society of Nephrology. Each group has posted a list of “Five things Physicians and Patients Should Question” at the website www.ChoosingWisely.org.

For example, the five “don’ts” specified by the AAFP are: (1) don’t do imaging for low back pain within the first six weeks unless red fl ags are present; (2) don’t routinely prescribe antibiotics for acute mild-to-moderate sinusitis unless symptoms last for seven or more days or symptoms worsen

20 THE CLINICAL ADVISOR • MAY 2012 • www.ClinicalAdvisor.com

after initial clinical improvement; (3) don’t use DEXA screening for osteoporosis in women younger than age 65 years or in men younger than age 70 years with no risk factors; (4) don’t order annual ECGs or any other cardiac screening for low-risk patients without symptoms; and (5) don’t perform Pap smears on women who are younger than age 21 years or who have had a hysterectomy for noncancer disease.

Each organization included additional details to explain when a particular test or treatment may be appropriate.

© ISTOCKPHOTO.COM / MEDIAPHOTOS

Check this list before ordering that test

Viral vs. bacterial sinusitis ALTHOUGH THE vast majority of sinus infections are caused by viruses, bacteria are likely to be the culprits in specific circumstances, and in those instances, antibiotics should be used.

This information comes from a new guideline issued by the Infectious Diseases Society of America (IDSA) focusing on acute bacterial rhinosinusitis in children and adults. Authored by a team led by Anthony W. Chow, MD, the guideline is available at www .idsociety.org and provides specific characteristics of the illness to help distinguish between viral and bacterial sinus infections.

According to the guideline, a sinus infection is likely to be caused by bacteria rather than a virus if any of the three following conditions is present: (1) symptoms last for at least 10 days without any evidence of clinical improvement; (2) symptoms are severe, including fever of 102°F or higher, and nasal discharge and facial pain enduring for at least

Symptoms that last for at least 10 days may indicate a bacterial infection.

three to four consecutive days at the beginning of illness; and (3) symptoms or signs worsen, as characterized by new fever or headache developing or nasal discharge increasing, typically after a viral upper respiratory infection that lasted five or six days and initially seemed to improve.

The IDSA guideline also suggests that a five- to seven-day course of antibiotics is long enough to treat the infection in adults without encouraging antibiotic resistance. Children, however, should undergo antibiotic treatment for 10 to 14 days.

Topical and oral decongestants and antihistamines should be avoided in patients with acute bacterial rhinosinusitis due to scant evidence that they hasten recovery; they may even induce inflammation in the nasal cavity, according to the guideline.

Symptoms should be managed by means of hydration, analgesics, antipyretics, saline irrigation, and intranasal corticosteroids.

© SCIENCE PHOTO LIB.

Tdap vaccination now okay for seniors, too The CDC’s Advisory Committee on Immunization Practices (ACIP) expanded its tetanus, diphtheria, and acellular pertussis (Tdap) vaccination recommendation to include persons aged 65 years and older.

Prior to this change, the shot was recommended only for adults aged 19 through 64 years. Vaccination in adults aged 65 years and older was generally recommended only for those who had close contact with an infant younger than age 12 months.

Now, the ACIP believes that providers should not miss an opportunity to administer the Tdap vaccine to persons aged 65 years and older.

In its updated guidance, ACIP calls for adults aged 19 years and older to receive a single dose of Tdap if they have never had the vaccine and recommends that Tdap be administered regardless of the interval since the last tetanus or diphtheria toxoidcontaining vaccine was received.

Be sure patients can identify nuts WHEN USING dietary avoidance to treat nut allergies, be sure that the patient can properly identify peanuts and tree nuts.

In a recent study, persons aged 6 years and older were asked to identify peanuts and nine tree nuts— including almonds, Brazil nuts, cashews, hazelnuts, Macadamia nuts, pecans, pine nuts, pistachios, and walnuts—displayed in 19 different forms. The 649 adults and 459 children who completed the study identified an average of 8.4 nuts (44.2%). Children aged 6 to 18 years were only able to identify a mean 4.6 nuts (24.2%), compared with 11.1 (58.4%) for adults older than age 18 years.

Half of people with a peanut or tree-nut allergy correctly identified all forms of nuts to which they were allergic, but these respondents performed no better than nonallergic subjects on the test. Furthermore, parents of children with nut allergies did no better than parents of nonallergic children.

“Overall, both children and adults are unreliable at visually identifying most nuts,” concluded Todd L. Hostetler, MD, and colleagues (Ann Allergy Asthma Immunol. 2012;108:25-29).

The most commonly identified items were peanuts in the shell and out of the shell. Hazelnuts both in the shell and out of the shell were the least commonly identified tree nut. ■

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MAY 2012 21

CME CE

PROGRAM OUTLINE MAY 2012

0.5 CREDITS

Page 23 FEATURE HAART meds: Implications for the older adult patient Teri Capriotti, DO, MSN, CRNP, and Sarah Sheerin Dr. Capriotti and Ms. Sheerin have no relationships to disclose relating to the content of this article.

■ LEARNING OBJECTIVES: • Name the medication that boosts the activity of some protease inhibitors (PIs) when added to a highly active antiretroviral therapy (HAART) regimen.

• Describe the most common adverse effect associated with HAART. • Identify the HAART medication associated with reductions in bone mineral density.

• Name the medication that is contraindicated in a patient taking PIs. 0.5 CREDITS

Page 59 DERMATOLOGY CLINIC Macules spread from abdomen to extremities Kerri Robbins, MD Dr. Robbins has no relationships to disclose relating to the content of this article.

Pink nodule on the crown of the head Esther Stern, NP-C Ms. Stern has no relationships to disclose relating to the content of this article.

■ LEARNING OBJECTIVES: • To identify and diagnose dermatologic conditions and review up-to-date treatment.

Page 65 DERMATOLOGIC LOOK-ALIKES Bimalar facial rashes Joe Monroe, MPAS, PA Mr. Monroe has no relationships to disclose relating to the content of this article.

■ LEARNING OBJECTIVE: • To distinguish and properly treat dermatologic conditions with similar presentations.

Page 70 POSTTEST

This program has been reviewed and is approved for a maximum of 1 hour of AAPA Category I CME credit by the Physician Assistant Review Panel. Approval is valid for one year from the issue date of May 2012. Participants may submit the self-assessment at any time during that period. This program was planned in accordance with AAPA’s CME Standards for Enduring Material Programs and for Commercial Support of Enduring Material Programs.

Nurse Practitioner Associates for Continuing Education (NPACE) is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s Commission on Accreditation. NPACE designates this educational activity for a maximum of 1 contact hour of credit. Participants should only claim credit commensurate with the extent of their participation in the activity.

22 THE CLINICAL ADVISOR • MAY 2012 • www.ClinicalAdvisor.com

■ LEARNING OBJECTIVES :

CME CE

• Name the medication that boosts the activity of some protease inhibitors (PIs) when added to a highly active antiretroviral therapy (HAART) regimen.

• Describe the most common adverse effect associated with HAART. • Identify the HAART medication associated with reductions in bone mineral density.

• Name the medication that is contraindicated in a patient taking PIs. ■ COMPLETE THE POSTTEST: Page 70 ■ ADDITIONAL CME/CE: Pages 59, 65

FEATURE

Turn to page 22 for additional information on this month’s CME/CE courses.

TERI CAPRIOTTI, DO, MSN, CRNP, AND SARAH SHEERIN

HAART meds: Implications for the older adult patient Patients infected with HIV are living longer, which means they have more age-related comorbidities that require other medications as well.

© MOLLY BORMAN-PULLEN

T

HAART medications can impact a patient’s digestion, increase insulin resistance, and decrease bone density.

he introduction of highly active antiretroviral therapy (HAART) has transformed HIV infection from a rapidly progressive life-threatening illness to a chronic manageable condition. More and more persons are growing older with HIV infection. The CDC estimates that more than 1 million people are living with HIV infection in the United States. Approximately 29% of those infected with HIV are older than age 50 years, and the number of older Americans with HIV infection is on the rise. In the next five years, the number of Americans older than age 50 years is projected to constitute 50% of those infected with HIV.1,2 The demographic shift in those affected

by HIV is attributed to the aging of the baby boom generation and to medical advancements in antiretroviral therapy that are allowing HIVinfected adults to remain productive longer. Older individuals with HIV are dealing with the effects of age while on HAART and will endure unique side effects because of their age, comorbidities, and other prescribed medications.3,4 According to

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MAY 2012 23

CME CE

HAART MEDICATIONS

some data, up to 75% of deaths among HIV-infected adults taking antiretroviral medications are due to comorbidities, not AIDs-defining conditions.5

CD4 T cell under attack by HIV

Fusion inhibitors work here.

CD4 T cell

Comorbidities of the HIV-positive older adult

With age comes physiologic changes as well as susceptibility to certain chronic diseases. Approximately 80% of older adults have at least one chronic health condition, and 50% have two or more. Cardiovascular conditions (e.g., hypertension, coronary artery disease, and stroke) are the most common causes of morbidity and mortality in the older age group.

Diabetes, hyperlipidemia, chronic obstructive pulmonary disease (COPD), and osteoporosis are also common in older adults. These conditions usually require prescription medications. Older adults commonly take four to five prescription medications in addition to OTC medications daily.6 For many HIV-positive older adults, HAART is added to a regimen of other medications. Researchers are attempting to answer questions about how HAART will affect the aging adult, influence comorbid conditions, and interact with other medications.

HAART medications and their mechanisms of action

The multidrug combinations of HAART can suppress the HIV viral load to undetectable levels and stop the destruction of CD4 T lymphocytes. There are six categories of HAART agents: nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), integrase strand transfer inhibitors (INSTIs), fusion inhibitors (FIs), and chemokine coreceptor 5 (CCR5) antagonists. The drugs in each category attempt to interrupt the life cycle of HIV at a different point, and when used together, there is an additive effect (Figure 1).7,8 Reverse transcriptase inhibitors (RTIs) block the activity of reverse transcriptase, an enzyme used by the virus to build new DNA from its RNA. PIs inhibit the activity of viral enzymes that cleave new proteins for final assembly into new HIV virions. Entry inhibitors, which include FIs and CCR5 antagonists, block entry of HIV into the cell membrane, preventing infection of uninfected cells.

Achieving viral suppression requires use of HAART regimens with three drugs from two or three different categories. Some HAART agents are available as fi xed-dose combinations in order to reduce the number of pills the patient must take. The current standard for formulating a HAART regimen recommends the use of either a PI or an NNRTI in combination with two NRTIs.9 The activity

Reverse transcriptase inhibitors work here to stop HIV RNA from turning into DNA. CCR5 antagonists work here.

Integrase strand transfer inhibitors work here to stop HIV DNA from integrating into CD4 DNA.

CD4 Receptor

Protease inhibitors work here to stop HIV protein assembly.

New HIV is released here.

FIGURE 1. Different points in the HIV life cycle at which HAART medications work

of some PIs is “boosted” by the addition of the PI ritonavir (Norvir) to the regimen. In this therapeutic strategy, a small dose of ritonavir is given concurrently with another PI to pharmacologically enhance the PI effect. For many of the PIs, ritonavir-boosting results in improved drug levels that can increase efficacy. However, increased exposure to PIs carries with it the potential for increased toxicity.10 Guidelines for the use of antiretroviral agents in adults infected with HIV-1 can be found at the AIDSinfo Web site.8 How does HAART affect the older adult?

As with many other medications, nausea and vomiting are common side effects associated with HAART. However, these symptoms are transient and can be alleviated by adjusting the patient’s mealtimes relative to medication administration. Allergy, a possible side effect of any medication, may also be experienced early in the HAART regimen. Different agents can be substituted when a patient is exhibiting signs of allergy.

The most common adverse effects associated with HAART involve metabolic abnormalities.11 Some HAART medications have direct effects on lipid metabolism, insulin utilization, and bone formation. Specific types of HAART medications are known to increase risk of cardiovascular disease (CVD), diabetes, and osteoporosis. Hepatotoxicity

24 THE CLINICAL ADVISOR • MAY 2012 • www.ClinicalAdvisor.com

has been shown to occur with HAART, mainly in patients with concomitant hepatitis B or hepatitis C. In some studies, nephrotoxicity is associated with HAART, but renal problems are often reversible with discontinuation of the drugs. HAART has also been linked to esophagitis and gastroesophageal reflux disease (GERD).12 Cardiovascular side effects. Patients on HAART are at increased risk of developing an unfavorable lipid profi le.

PIs and NNRTIs have been associated with dyslipidemia (elevated serum triglyceride, total cholesterol, and LDL levels and reduced HDL levels). The clinician needs to educate patients about cardioprotective nutrition and exercise.

A condition known as lipodystrophy affects 40% to 80% of persons with HIV who are being treated with HAART.13-16 Lipodystrophy is a disturbance in the way the body produces, uses, and stores fat. There are two different kinds of lipodystrophy: lipoatrophy and lipohypertrophy. In lipoatrophy, fat is lost from particular areas of the body, particularly the arms, legs, face, and buttocks. In lipohypertrophy, also known as hyperadiposity, fat accumulates in particular parts of the body, especially the abdomen, breasts, and back of the neck.

Lipodystrophy is often accompanied by insulin resistance, hyperinsulinemia, and hyperglycemia. The metabolic disturbances and central fat accumulation are the same as those seen in metabolic syndrome, a condition that predisposes a person to CVD and diabetes.11,17,18 Insulin resistance and diabetes. The prevalence of hyperglycemia and diabetes mellitus is significantly higher in persons treated with HAART than in the general population.

Insulin resistance was one of the first metabolic complications reported with HAART. Specific antiretrovirals can increase insulin resistance through two principal mechanisms: either directly, by interfering with insulin signaling at the cellular level; or indirectly, as a consequence of lipodystrophy and associated metabolic syndrome.19 Although PIs are the drug class usually implicated in insulin resistance, some studies have shown an association between increased risk of diabetes and cumulative exposure to NRTIs.20 Given the current epidemics of obesity and diabetes in this country, PIs and NRTIs should be used with caution in patients at risk of diabetes. Periodic measurement of body weight and lipid and glucose levels is necessary. Insulin resistance can result in hyperglycemia.

Effects on bone. Osteopenia and osteoporosis resulting from decreased bone mineral density (BMD) have been found in patients taking HAART. Results of a recent investigation of 670 adults on HAART who were followed for five years showed that osteopenia developed in 18% and osteoporosis

developed in 29%. Factors associated with bone loss were age, male sex, low BMI, and use of specific HAART agents (PIs, NRTIs, and NNRTIs).21 Some of the strongest data regarding the association of HAART with BMD reductions have been observed with the NRTI tenofovir (Viread).

Tenofovir treatment has been shown not only to decrease BMD but to increase urinary calcium excretion as well.22,23 Hip fracture is more common in HIV-positive adults on HAART than in the general population. Bisphosphonates (such as alendronate [Fosamax]), calcium, and vitamin D have been shown to prevent bone loss.24 In addition, the patient should be encouraged to undergo annual dual-energy x-ray absorptiometry to measure BMD, and weight-bearing exercises should be prescribed to enhance bone strength.

GI effects. HAART has also been associated with gastroesophageal reflux and esophagitis. A recent research investigation reviewed endoscopies of 706 HIV-infected patients; 467 of the patients were on HAART and 239 were not. Significant increases were seen over time in the frequencies of reflux symptoms, GERD, infl ammatory gastropathy, gastric ulcer, and Helicobacter pylori infection in those treated with HAART.12 Esophagitis, gastritis, and GERD are common in patients older than age 50 years. Individuals often take OTC medications, such as histamine2-receptor blockers (e.g., cimetidine [Tagamet]) or proton pump inhibitors (e.g., lansoprazole [Prevacid]). HAART-treated individuals may take these OTC drugs without understanding that significant drugdrug interactions can occur. Taking a gastric acid-reducing agent can lower blood concentrations of HAART, which may lead to inadequate viral suppression or adverse events.

Studies indicate that the PIs atazanavir (Reyataz) and nelfinavir (Viracept) are contraindicated with many acidsuppressive drugs. Educating patients about the importance of reporting the use of any acid-reducing agents, whether prescription or OTC, is essential to optimizing the treatment of HIV disease.

The incidence of drug-induced liver toxicity is not wellknown for most antiretroviral medications. Moreover, the contribution of each particular drug in an HAART regimen to the development of hepatotoxicity is difficult to determine.

One of the liver abnormalities linked to the use of antiretrovirals is the elevation of liver aminotransferases. Liver toxicity is more frequent among subjects with chronic hepatitis C and/or B. Liver disease is now the most common nonAIDS-related cause of death among HIV-infected patients, accounting for 14% to 18% of all deaths in this population.25 Continues on page 26

www.ClinicalAdvisor.com â&#x20AC;˘ THE CLINICAL ADVISOR â&#x20AC;˘ MAY 2012 25

CME CE

HAART MEDICATIONS

TABLE 1. HAART drug-drug interactions HIV drug category

Names of drugs

Common drug-drug interactions

Chemokine coreceptor 5 (CCR5) antagonist

• Maraviroc (Selzentry)

• Data still being collected; multiple drug-drug interactions. See prescription directions.

Fusion inhibitor (FI)

• Enfuvirtide (Fuzeon)

• Few drug-drug interactions

Integrase strand transfer inhibitor (INSTI)

• Raltegravir (Isentress)

• Few drug-drug interactions

Non-nucleoside reverse transcriptase inhibitor (NNRTI)

• Delavirdine (Rescriptor) • Efavirenz (Sustiva) • Eltravirine (Intelence) • Nevirapine (Viramune) • Rilpivirine (Edurant)

• Use caution with statin drugs; may increase statin level in blood. Monitor liver function and possible myopathy, rhabdomyolysis.

• Use caution with warfarin; may increase or decrease warfarin effects.

• Use caution with clopidogrel (Plavix). may decrease effects of clopidogrel.

Contraindicated. with dabigatran (Pradaxa) and rivaroxaban (Xarelto).

Nucleotide reverse transcriptase inhibitor (NRTI)

• Abacavir (Ziagen) • Didanosine (Videx) • Emtricitabine (Emtriva) • Lamivudine (Epivir) • Stavudine (Zerit) • Tenofovir (Viread) • Zalcitabine (Hivid) • Zidovudine (Retrovir)

• Use caution with chlorpropamide (Diabinese), insulin resistance may increase risk of hyperglycemia.

Protease inhibitor (PI)

• Atazanavir (Reyataz) • Darunavir (Prezista) • Fosamprenavir (Lexiva) • Indinavir (Crixivan) • Lopinavir • Nelfinavir (Viracept) • Ritonavir (Norvir) • Saquinavir (Invirase) • Tipranavir (Aptivus)

• Use caution with statin drugs; may increase statin level in blood. Monitor liver function and possible myopathy, rhabdomyolysis.

• Use caution with warfarin; may increase or decrease warfarin effects.

• Use caution with clopidogrel; may decrease effects of clopidogrel. Contraindicated with dabigatran and rivaroxaban.

• Use proton pump inhibitors and histamine2-receptor blockers with caution.

• Use caution with insulin; insulin resistance may increase risk of hyperglycemia.

• Use caution with digoxin; can potentiate or antagonize digoxin.

• Can increase calcium channel antagonist effect; monitor for hypotension, arrhythmias.

• Use caution with beta blockers.

• Erectile dysfunction drugs are contraindicated.

Discerning the number of individual factors that may contribute collectively to liver damage is difficult in patients receiving antiretroviral therapy. Several drugs are combined in a given HAART regimen, making the attribution of hepatotoxicity to a particular drug challenging. Moreover, HIV-infected patients also may be receiving concurrent medications with potential for liver toxicity, such as antituberculosis (anti-TB) drugs, lipid-lowering agents, antifungals, antibiotics, and anticonvulsants.26 Periodic monitoring of liver enzymes is crucial.

Nephrotoxicity. The antiretroviral agents most strongly associated with direct nephrotoxicity include the NRTI tenofovir and the PI indinavir (Crixivan). Tenofovir and related nucleoside analogs have primarily been associated with proximal tubular dysfunction and acute kidney injury, whereas indinavir and atazanavir are known to cause nephrolithiasis, obstructive nephropathy, and interstitial nephritis.

Periodic measurement of serum creatinine is required.

Patients with preexisting chronic kidney disease require close monitoring, dose modification, and avoidance or cautious use of potentially nephrotoxic medications. Kidney damage related to antiretroviral therapy is typically reversible with early recognition and timely discontinuation of the offending agent.27 Lactic acidosis. A rare side effect, lactic acidosis has been associated with HAART, particularly the NRTIs. The mechanism of NRTI-induced lactic acidosis is thought to be secondary to mitochondrial toxicity. Risk factors associated with increased incidence of lactic acidosis in HIV-infected patients include female sex, high-dose didanosine (Videx) or stavudine (Zerit), impaired renal clearance, low CD4 T-cell count prior to initiation of NRTI therapy, and concomitant hepatitis B or hepatitis C. Patients present with weakness, fever, abdominal pain, nausea, vomiting, and dyspnea.

26 THE CLINICAL ADVISOR • MAY 2012 • www.ClinicalAdvisor.com

HAART is effective only when the patient adheres to the recommended daily course of therapy. Failure to do so is a substantial barrier to its success.

Laboratory findings include elevations in liver enzymes, serum lactic acid, amylase, lipase, and creatine kinase. Drug discontinuation will be necessary.28 Possible drug-drug interactions

While drug interactions with HAART have been widely investigated for the PIs, information continues to emerge regarding NRTI and NNRTI drug interactions. However, there are fewer clinical data for the FIs, CCR5 antagonists, and the INSTIs (Table 1).

Anti-TB drugs. Tuberculosis is one of the most common opportunistic infections that occur in HIV-positive patients.

Therefore, many HIV-positive patients require anti-TB drug treatment. Most interactions between HAART and anti-TB agents as well as other antimycobacterial drugs occur through the stimulation or inhibition of liver enzymes that make up the cytochrome P (CYP) 450 system. Rifampin and rifabutin (Mycobutin), used for the treatment of TB, are strong stimulants of the CYP450 enzyme system in the liver. Stimulation of the CYP450 enzymes causes increased breakdown of HAART agents. Concurrent administration of anti-TB drugs with PIs, NNRTIs, INSTIs, or CCR5 antagonists can decrease blood concentrations of the HAART agents.

Rifabutin is a less potent inducer of CYP450 than rifampin and may be used as an alternative. There are no major interactions between rifampin or rifabutin and the NRTIs abacavir (Ziagen), emtricitabine (Emtriva), didanosine, lamivudine (Epivir), tenofovir, or zidovudine (Retrovir).29 Both HAART and antimycobacterial agents can have toxic side effects. Some of the toxic effects of antiretrovirals and anti-TB drugs are the same, making it difficult to determine the causative drug. Patients with chronic liver disease have higher rates of toxicity and need more frequent monitoring of liver function tests.

Antihyperlipidemia (statin) drugs. 3-hydroxymethylglutaryl-coenzyme A (HMGCoA) reductase inhibitors, commonly known as statins, are antihyperlipidemia drugs often used in HIV-positive patients. Patients living with HIV are at risk for dyslipidemia as a result of the HIV itself and from treatment with PIs and NNRTIs.30 The statins are extensively metabolized by the liver CYP450 system, as are HAART agents. Drug-drug interactions between the statins and antiretroviral therapy must be considered when treating HIV or dyslipidemia. Liver toxicity is a possible side effect of both HAART and statins.31 High blood concentrations

of statins have also been associated with rhabdomyolysis, the breakdown of muscle tissue. When statins are needed, the lowest effective dosage should be used. Simvastatin (Zocor) and lovastatin (Mevacor), commonly used statin agents, are contraindicated with the use of PIs.32 Antihypertensives. Hypertension is common in patients older than age 50 years. The clinician should be aware of the potential interaction between PIs and beta blockers as well as between PIs and calcium channel blockers.

GI drugs. Concomitant use of acid-reducing drugs and HAART is common.33 A significant drug interaction occurs between PIs and proton pump inhibitors and histamine2receptor antagonists that are used to treat esophagitis and GERD. Acid-reducing agents decrease plasma PI concentrations, which can lead to inadequate viral suppression. The bioavailability of fosamprenavir (Lexiva), indinavir, lopinavir, nelfinavir, and tipranavir (Aptivus) has been reported to be negatively affected to varying degrees by certain acidreducing agents.34 All proton pump inhibitors (e.g., lansoprazole) and histamine2-receptor blockers (e.g., cimetidine [Tagamet]) should be used with caution when prescribed for patients taking HAART. Proton pump inhibitors should not be administered with the PIs atazanavir or nelfinavir or with the NNRTI rilpivirine (Edurant). A comprehensive list of drug-drug interactions with HAART is available from the University of Liverpool HIV Pharmacology Group.32 Care of patients on HAART

HAART is a multidrug regimen that is effective only when the patient adheres to the recommended daily course of therapy. Failure to adhere to treatment is a substantial barrier AT A GLANCE ●

Older individuals with HIV are dealing with the effects of age while on HAART and will endure unique side effects because of their age, comorbidities, and other prescribed medications.

●

Each category of drugs attempts to interrupt the life cycle of HIV at a different point, and when used together, there is an additive effect.

●

The current standard for formulating a HAART regimen recommends the use of either a PI or an NNRTI in combination with two NRTIs.

●

Clinicians should also be aware of increased depression, which often develops in HIV-positive patients.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MAY 2012 27

CME CE

HAART MEDICATIONS

Patients who develop resistance can be changed to another drug in the same class; however, resistance often occurs across drug categories. to its success. In addition, maximal efficacy of HAART requires adequate drug absorption and bioavailability. Lack of compliance in taking medications as prescribed diminishes viral suppression and allows the virus to mutate and develop resistance. Drug resistance is one of the most significant threats to effective therapy. Patients who develop resistance can be changed to another drug in the same class; however, resistance often occurs across drug categories. Laboratory tests are performed when patients are not responding to drug treatment. Genotyping tests detect viral mutation, and phenotyping tests detect a reduction in the sensitivity of the virus to the drugs.35 Clinicians need to provide education and support to patients on HAART. Begin by explaining the importance of adhering to the regimen, and devise a medication schedule that works with the patient’s daily routine. Pillboxes and cell phones or other devices can be used to remind the patient of medication times. Patients on the FI enfuvirtide (Fuzeon) need instruction regarding self-injection and rotation of injection sites. For follow-up of all patients on HAART medications, periodic telephone counseling can be helpful.

In addition to monitoring patients for comorbidities associated with HAART and the drug-drug interactions previously discussed, clinicians should be aware of increased depression, which often develops in HIV-positive patients. The low emotional state is associated with nonadherence to the medication regimen. In order to inspire hope, educate patients regarding the ability of HAART to strongly suppress viral replication and increase CD4 T-cell counts. Individuals need to understand that HIV is a chronic disorder that is manageable with new treatments. Antidepressants have been shown to increase patient compliance with the HAART regimen. Be sure to inform patients that the OTC supplement St. John’s wort is contraindicated with all PIs, as are all erectile dysfunction drugs. Tricyclic antidepressants and selective serotonin reuptake inhibitorss should be used with caution by patients on HAART. HAART, particularly PIs, can cause elevated blood levels of some antidepressants and lead to toxicity.36

HIV-infected population will be experiencing age-related disorders. Adults on HAART are now living into old age with HIV. Older HIV-infected adults face unique health challenges stemming from age-related changes to the body that are accelerated by HIV infection, the side effects of HAART, and treatments for age-associated illnesses.

HAART is composed of a combination of three or four drugs from different categories: RTIs, PIs, INSTIs, CCR5 antagonists, and FIs. The medications of HAART complement each other and are taken together to produce an additive effect. However, drug-drug interactions can occur when HAART is used with other medications. Because many older adults have comorbid conditions, they commonly take four to five prescription drugs plus OTC medications daily. These prescription drugs are essential for such chronic conditions as CVD, diabetes, hypertension, COPD, and/ or osteoporosis. With the population of HIV-positive older adults on the rise, clinicians need to be aware of the possible side effects of HAART and how other drugs interact with it. A growing body of research is emerging regarding the adverse effects, contraindications, and drug-drug interactions of the HIV medications. PIs have been well-investigated, but more data are needed regarding the side effects and interactions of drugs from the other medication categories that make up HAART. ■ Dr. Capriotti is a clinical associate professor in the Villanova University College of Nursing, Villanova, Pa., where Ms. Sheerin is a junior honors student.

References 1. Centers for Disease Control and Prevention. HIV/AIDS among persons aged 50 and older. Available at www.cdc.gov/hiv/topics/over50/resources/ factsheets/over50.htm.

2. Centers for Disease Control and Prevention. HIV surveillance report: Diagnoses of HIV infection and AIDS in the United States and dependent areas, 2009. Available at www.cdc.gov/hiv/topics/surveillance/basic.htm.

3. Vance DE, McGuinness T, Musgrove K, et al. Successful aging and the

Summary

Estimates indicate that by 2015, nearly half of individuals living with HIV in the United States will be 50 years of age or older. In the past, HIV-infected patients were mainly a young cohort of the population. Because of the increase in life expectancy of patients receiving HAART, however, the 28 THE CLINICAL ADVISOR • MAY 2012 • www.ClinicalAdvisor.com

WHAT DO YOU THINK? Add your comments to this article —or any article — by going to www.ClinicalAdvisor.com.You will also see what your colleagues are saying.

epidemiology of HIV. Clin Interv Aging. 2011;6:181-192. Available at www

20. Aboud M, Elgalib A, Kulasegaram R, Peters B. Insulin resistance and

.ncbi.nlm.nih.gov/pmc/articles/PMC3147048/.

HIV infection: a review. Int J Clin Pract. 2007;61:463-472.

4. Vance DE. Aging with HIV: clinical considerations for an emerging popu-

21. Bonjoch A, Figueras M, Estany C, et al. High prevalence of and progres-

lation. Am J Nurs. 2010;110:42-47.

sion to low bone mineral density in HIV-infected patients: a longitudinal

5. San Francisco AIDS Foundation. HIV/AIDS and aging: emerging issues

cohort study. AIDS. 2010;24:2827-2833.

in research, care, treatment, and prevention. Available at www.sfaf.org/

22. Mansky KC. Aging, human immunodeficiency virus, and bone health.

hiv-info/hot-topics/hivision/hiv-and-aging-vienna-satellite-2010-07-19-

Clin Interv Aging. 2010;5:285-292. Available at www.ncbi.nlm.nih.gov/pmc/

executive-summary.pdf.

articles/PMC2946855/.

6. Gu Q, Dillon CF, Burt VL. Prescription drug use continues to increase:

23. Jhaveri MA, Mawad HW, Thornton AC, et al. Tenofovir-associated

U.S. prescription drug data for 2007-2008. Available at www.cdc.gov/nchs/

severe bone pain: I cannot walk! J Int Assoc Physicians AIDS Care (Chic).

data/databriefs/db42.pdf.

2010;9:328-334.

7. National Institutes of Health. FDA-approved anti-HIV medications.

24. Guaraldi G, Orlando G, Madeddu G, et al. Alendronate reduces

In: HIV and Its Treatment. Available at aidsinfo.nih.gov/contentfiles/

bone resorption in HIV-associated osteopenia/osteoporosis. HIV Clin

HIVandItsTreatment_cbrochure_en.pdf.

Trials. 2004;5:269-277. Available at thomasland.metapress.com/content/

8. National Institutes of Health. Guidelines regarding treatment of adults

md8v5dlgen3tbrhx/fulltext.pdf.

and adolescents with HIV infection/AIDS. Available at aidsinfo.nih.

25. Price JC, Thio CL. Liver disease in the HIV-infected individual. Clin

gov/guidelines/html/1/adult-and-adolescent-treatment-guidelines/14/

Gastroenterol Hepatol. 2010;8:1002-1012. Available at www.ncbi.nlm.nih.

considerations-for-antiretroviral-use-in-special-patient-populations.

gov/pmc/articles/PMC2997131/.

9. New York State Department of Health AIDS Institute and Johns

26. Núñez M. Clinical syndromes and consequences of antiretroviral-

Hopkins University Division of Infectious Diseases. HIV clinical resource.

related hepatotoxicity. Hepatology. 2010;52:1143-1155.

Available at www.hivguidelines.org.

27. Izzedine H, Harris M, Perazella MA. The nephrotoxic effects of

10. Leider J, LeLacheur SF, Stewart J. Identifying and co-managing the

HAART. Nat Rev Nephrol. 2009;5:563-573.

HIV-infected adult: a guidebook for the primary care clinician. The Clinical

28. Patel V, Hedayati SS. Lactic acidosis in an HIV-infected patient receiving

Advisor. 2011;Suppl S1-S35.

highly active antiretroviral therapy. Nat Clin Pract Nephrol. 2006;2:109-114.

11. Brown TT, Glesby MJ. Management of the metabolic effects of HIV and

Available at www.nature.com/nrneph/journal/v2/n2/full/ncpneph0102.html.

HIV drugs. Nat Rev Endocrinol. 2011;8:11-21.

29. Pozniak AL, Collins S, Coyne KM, et al. British HIV Association guidelines

12. Nkuize M, De Wit S, Muls V, et al. Upper gastrointestinal endoscopic find-

for the treatment of TB/HIV co-infection 2009. Available at www.bhiva.org/

ings in the era of highly active antiretroviral therapy. HIV Med. 2010;11:412-417.

documents/Guidelines/TB/hiv_954_online_final.pdf.

13. Mercier S, Gueye NF, Cournil A, et al. Lipodystrophy and metabolic disor-

30. Blanco F, San Román J, Vispo E, et al. Management of metabolic complica-

ders in HIV-1-infected adults on 4- to 9-year antiretroviral therapy in Senegal:

tions and cardiovascular risk in HIV-infected patients. AIDS Rev. 2010;12:231-

a case-control study. J Acquir Immune Defic Syndr. 2009;51;224-230.

241. Available at www.aidsreviews.com/files/2010_12_4_231-241.pdf.

14. Freitas P, Carvalho D, Souto S, et al. Impact of lipodystrophy on the

31. Ray GM. Antiretroviral and statin drug-drug interactions. Cardiol Rev.

prevalence and components of metabolic syndrome in HIV-infected

2009;17:44-47.

patients. BMC Infect Dis. 2011;11: 246. Available at www.biomedcentral.

32. University of Liverpool Pharmacology Group, UK. HIV drug interac-

com/1471-2334/11/246.

tions. Available at www.hiv-druginteractions.org.

15. Chen D, Misra A, Garg A. Clinical review 153: lipodystrophy in human

33. van Lunzen J, Liess H, Arastéh K, et al. Concomitant use of gastric acid-

immunodeficiency virus-infected patients. J Clin Endocrinol Metab. 2002;87;

reducing agents is frequent among HIV-1-infected patients receiving

4845-4856. Available at jcem.endojournals.org/content/87/11/4845.long.

protease inhibitor-based highly active antiretroviral therapy. HIV Med.

16. Barbaro G. Visceral fat as target of highly active antiretroviral therapy-

2007;8:220-225.

associated metabolic syndrome. Curr Pharm Des. 2007;13;2208-2213.

34. Falcon RW, Kakuda TN. Drug interactions between HIV protease

17. Aberg JA. Cardiovascular complications in HIV management: past,

inhibitors and acid-reducing agents. Clin Pharmacokinet. 2008;47:75-89.

present, and future. J Acquir Immun Defic Syndr. 2009;50:54-64. Available at

35. Feinberg J. Management of newly diagnosed HIV infection. Ann Intern

www.ncbi.nlm.nih.gov/pmc/articles/PMC2746916/.

Med. 2011;155: ITC41.

18. Kotler DP. HIV and antiretroviral therapy: lipid abnormalities and

36. Watkins CC, Pieper AA, Treisman GJ. Safety considerations in drug

associated cardiovascular risk in HIV-infected patients. J Acquir Immune Def

treatment of depression in HIV-positive patients: an updated review.

Syndr. 2008;49 Suppl 2:S79-S85.

Drug Saf. 2011;34:623-639.

19. Feeney ER, Mallon PW. Insulin resistance in treated HIV infection. Best Pract Res Clin Endocrinol Metab. 2011;25:443-458.

All electronic documents accessed April 15, 2012.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MAY 2012 29

Derm Dx

EXCLUSIVE TO THE WEB

INTERACT WITH YOUR PEERS by viewing the images and offering your diagnosis and comments. To post your answer, obtain more clues, or view similar cases, visit ClinicalAdvisor.com/DermDx. Learn more about diagnosing and treating these conditions, and see how you compare with your fellow colleagues.

Unilateral pink rash on the left side A boy, age 5 years, presented with a rash around his left armpit, torso, and upper arm that had been present for seven days, according to his mother.

WHAT IS YOUR DIAGNOSIS?

• • • •

Allergic contact dermatitis Unilateral laterothoracic exanthem Chickenpox Fifth disease

● See the full case at ClinicalAdvisor.com/DermDx0512A

Bright pink malar rash A girl, age 5 years, presented with a rash on her cheeks that had been present for one day. The girl’s mother thought the rash was likely an allergic reaction to a new product.

WHAT IS YOUR DIAGNOSIS?

• • • •

Contact dermatitis Fifth disease Hand-foot-mouth disease Sixth disease

● See the full case at ClinicalAdvisor.com/DermDx0512B

Have you missed any recent Derm Dx cases? Go to ClinicalAdvisor.com/DermDx for a complete archive of past quizzes as well as additional images of last month’s other cases.

Red plaque with ulceration

Asymptomatic eruption on the back

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MAY 2012 50

SPECIAL REPORT: JOE KOPCHA

SALARY SURVEY How are you doing?

With tax season comfortably in the rearview mirror for most, it’s the perfect time to assess your current financial situation. Thanks to the more than 9,000 nurse practitioners and physician assistants who participated in our second annual salary survey (nearly twice as many as last year), you can see how your income compares with that of your peers. We hope, you will be pleased with the result. If not, find a male dermatology PA with 20 or more years of experience working at an urban hospital in the West—he should be able to float you a loan.

Practice area

Family/adult medicine practitioners represented the most common practice area between both NP (Table 1) and PA (Table 2) respondents. In a departure from last year, geriatric medicine appeared among the top five NP practice areas, replacing obstetrics/ gynecology.The PA list remained unchanged.

TABLE 1. Average NP salary by practice area

TABLE 2. Average PA salary by practice area

Practice area

Response percent

Average salary

Practice area

Response percent

Average salary

Family/adult medicine

33.5%

$85,974

Family/adult medicine

24%

$89,044

Pediatrics

6.1%

$77,282

Emergency medicine

9.5%

$107,904

Women’s health

5.1%

$78,390

Orthopedic medicine

7.1%

$100,265

Geriatric medicine

4.1%

$92,503

Urgent care

4.6%

$98,331

Oncology/hematology

3.8%

$94,831

Dermatology

3.7%

$110,204

Experience

As we saw last year, experience has little bearing on salary among NPs beyond the first five years of practice (Table 3). More experienced PAs see a slightly larger bump in income as their careers progress (Table 4).

TABLE 3. Average NP salary by experience level

TABLE 4. Average PA salary by experience level

Years of experience

Response percent

Average salary

Years of experience

Response percent

Average salary

<5

31.7%

$84,944

<5

39.9%

$88,657

6-10

20.8%

$89,834

6-10

20.7%

$98,031

11-15

22.7%

$91,632

11-15

15.2%

$100,186

16-20

11.6%

$90,693

16-20

7.7%

$100,017

>20

13.2%

$88,528

>20

16.5%

$101,916

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MAY 2012 33

SALARY SURVEY 2012

Sex

The majority of NP and PA respondents were once again women (92.1% and 66.2%, respectively).

Men continue to outearn women across the board. The average male NP earned $100,316 last year, compared with $87,393 for a female. This discrepancy was even more pronounced for PAs: Men earned $105,902 on average, whereas women earned $89,728.

Geographic region

Using the U.S. Census Bureau’s regional designations, the South was heavily represented among survey respondents (Figures 1 and 2). Average salaries had only slight regional variance, particularly among PAs. FIGURE 1. Average NP salary by geographic region

FIGURE 2. Average PA salary by geographic region

West

Midwest

Northeast

West

Midwest

Northeast

16.49% response $93,353 average salary

21.86% response $85,579 average salary

21.91% response $93,461 average salary

22.47% response $98,765 average salary

20.12% response $92,342 average salary

22.26% response $92,461 average salary

South

South

39.74% response $88,766 average salary

35.15% response $96,638 average salary

Practice setting

In a near duplication of last year’s results, office-based NPs (Table 5) and PAs (Table 6) were best represented in our survey. While hospital-based NPs earned higher salaries than office-based NPs, the opposite was true for PAs. TABLE 6. Average PA salary by practice setting

Practice setting

Percent response

Average salary

Practice setting

Percent response

Average salary

Office

24.7%

$84,568

Office

23.6%

$101,568

Clinic–standalone

16.7%

$85,418

Clinic–standalone

22.7%

$91,833

18.8%

$93,023

Clinic–hospital

15.7%

$93,421

Clinic–hospital

Hospital

14.2%

$98,288

Hospital

16.0%

$95,720

Walk-in/ambulatory

5.6%

$85,585

Walk-in/ambulatory

3.7%

$92,052

Practice location

Urban clinicians earned slightly higher salaries than their suburban and rural counterparts. Among NP respondents, 40.8% described their work environment as urban (average salary $91,295), 35.0% as suburban (average salary $87,561), and 24.2% as rural (average salary $85,579). The PA audience broke down as 40.7% urban (average salary $96,087), 40.4% suburban (average salary $94,734), and 18.9% rural (average salary $95,042).

34 THE CLINICAL ADVISOR • MAY 2012 • www.ClinicalAdvisor.com

© ISTOCKPHOTO.COM / VADYM NECHYPORENKO

TABLE 5. Average NP salary by practice setting

Job mobility

The proportion of NPs (Figure 3) and PAs (Figure 4) who move from job to job throughout the week was nearly identical to what was shown in last year’s survey.

FIGURE 3. Do you work at multiple locations (NPs)?

36.5% 63.5%

FIGURE 4. Do you work at multiple locations (PAs)?

38.6%

Yes 61.4%

No

Yes No

History and the future

Overall, clinicians remain optimistic about their financial future. In a slight uptick from last year’s results, just over 46% of NPs (Figure 5) and 50% of PAs (Figure 6) reported an increase in income over last year.

FIGURE 5. Did you earn more money this year (NPs)?

FIGURE 6. Did you earn more money this year (PAs)?

More 46.3%

More

40.0%

50.7%

Less Same

13.7%

34.5% Less Same

14.8%

When asked about their predictions for next year, the vast majority of NPs (Figure 7) and PAs (Figure 8) expect their income to rise or remain flat.

FIGURE 7. Do you expect to earn more money next year (NPs)?

FIGURE 8. Do you expect to earn more money next year (PAs)?

More 49.8%

More

46.2%

55.7%

Less Same 4.0%

40.5% Less Same

3.8%

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MAY 2012 35

SALARY SURVEY 2012

Weekly output

In addition to requests for financial information, we included a couple of questions to give us a sense of the average clinician’s workweek. Just like last year, there was little variation in the number of hours our readers put in. On average, approximately 80% of NPs and PAs work between 30 and 50 hours per week.

A more diverse picture emerged with regard to the number of patients seen per week, but the NP (Figure 9) and PA (Figure 10) breakdowns remained similar.

FIGURE 9. Number of patients seen per week (NPs) 3.4%

FIGURE 10. Number of patients seen per week (PAs)

6.5%

6.2%

9.3%

>125 14.6%

17.4%

>125 10.9%

101-125 76 -100

31.6%

22.7% 25.4%

51-75 26.5%

101-125 76 -100 51-75

26 -50

26-50

25.5%

≤ 25

≤ 25

Finally, prescription-writing behavior stayed consisted across all disciplines. More than two thirds of NPs (Figure 11) and PAs (Figure 12) write fewer 75 prescriptions per week.

FIGURE 11. Number of prescriptions written per week (NPs) 3.6%

FIGURE 12. Number of prescriptions written per week (PAs)

7.6%

5.3%

9.5%

201-250+ 16.4% 36.1%

201-250+

126-200 76-125

126-200 18.0%

31.1%

26-75 36.3%

0-25

Congratulations

The winner of the random drawing for a $50 American Express Gift Cheque is Marianne Adolf, a women’s health NP from Hazelwood, Mo. Consider it a head start on next year’s income. Thanks to all who participated in this exercise.

Mr. Kopcha is the editor of The Clinical Advisor.

36 THE CLINICAL ADVISOR • MAY 2012 • www.ClinicalAdvisor.com

76-125 26-75

36.1%

0-25

FEATURE: BETSY B. DOKKEN, NP, PHD

Optimizing technology for diabetes care Advancements in diabetes care abound, but busy practice schedules make staying current difficult. Follow these strategies to stay ahead.

I

n the real world, primary-care clinicians have only a few minutes during each appointment to devote to helping patients with diabetes improve glycemic control. The wise use of today’s technology can help make the most of those minutes. This article reviews some of the diabetes-related technologies available to patients and providers and recommends strategies providers can use to optimize patient care.

© BSIP / PHOTO RESEARCHERS, INC.

Blood glucose monitors

Blood glucose monitoring is recommended for patients with type 2 diabetes who take insulin.

With more than 60 models of blood glucose monitors on the market, most providers are unable to keep up with the details of all of them.1 In choosing a blood glucose monitor, consider the patients’ insurance coverage to ensure that he or she will not have to pay out of pocket for test strips, which cost about $1 each. Typically, as long as the patient uses a system that is included in the insurance plan’s formulary, the copayment is affordable. A good strategy to follow if you’re not sure what system to prescribe is to write nonbranded prescriptions for a “blood glucose monitoring kit” and “blood glucose test strips.” This gives the patient and the pharmacy some flexibility in choosing the brand based on features the patient prefers while keeping the copayment affordable.

The amount of digital storage in blood glucose monitors varies. Most providers focus on analyzing the most recent records. This is rational, not only because time is limited but also because clinicians need to respond to what is happening now, not what happened a month ago. Digital www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MAY 2012 37

storage of blood glucose results will help improve glycemic control only if those results are analyzed systematically. Some manufacturers provide free data-management software programs to patients, while others require the programs to be purchased separately. These programs allow patients to record such aspects of their diabetes regimen as insulin types and dosages, carbohydrate intake, and physical activity.

Encourage patients who rely on a monitor’s digital memory (in lieu of a paper log) to download their results on a regular basis to analyze the data for patterns. A list of blood glucose results without corresponding information on medications, meal timing, carbohydrate intake, and unusual physical activity is often more confusing than beneficial to diabetes management. The time-and-date stamp on the patient’s monitor must also be set correctly to interpret the electronic records.

In the clinic, using the monitor’s memory to influence management decisions can be tricky. Once the intake process is complete, downloading the meter and reviewing the electronic data takes too long to be considered during that appointment. Moreover, scrolling back in the monitor’s memory produces a string of meaningless numbers.

One practical approach is to include a meter download in the intake process. Typically, sales representatives from the manufacturing companies are eager to train clinic staff in how to download data from patients’ blood glucose monitors. The provider can choose the amount of data and the preferred format for the printout, and staff members can present this report with the patient’s intake history. Having this information at the beginning of the visit can mean the difference between a productive visit and a futile one.

Does self-monitoring improve glycemic control?

Although blood glucose monitoring is not exactly new technology, confusion still lingers regarding its usefulness.

The literature in this area is controversial.2-7 Blood glucose monitoring is the standard of care in patients with type 1 diabetes and is recommended for patients with type 2 diabetes who take insulin.8 Clinicians typically use their own judgment when advising monitoring to patients with type 2 diabetes who are not taking insulin. Consider whether the patient is at risk for hypoglycemia. (If the patient is taking a sulfonylurea, monitoring should be available to identify and/or prevent hypoglycemia.) Another factor influencing the decision to monitor is how the results will be used to improve glycemic control. For example, if the patient’s current treatment includes adjustment of basal insulin, the clinician may need only one fasting blood glucose result per day. If the current plan is to tailor carbohydrate amount or

© PHOTOTAKEUSA.COM / KEVIN A. SOMERVILLE

DIABETES TECHNOLOGY

FIGURE 1. Insulin-connecting peptide, or C-peptide, is the connector between the two chains of the proinsulin molecule.

prandial therapy to target postprandial glycemic control, preprandial and postprandial blood glucose testing will be necessary. Because this technology is expensive, blood glucose results should be requested only when they will affect clinical decision making or patient self-management.

Patients who are willing and able to adjust their lifestyle choices and diabetes treatment based on glucose results receive vastly more benefit from monitoring blood glucose than those who are not. Until patients can autonomously make lifestyle and treatment adjustments, diabetes educators can assist primary-care providers in training patients to analyze and interpret blood glucose test results.

Lancets and lancing devices

Most patients report that blood glucose monitoring is more difficult than taking insulin injections. Finger-sticks are painful, and minimizing this pain may lead to improved patient adherence to the treatment plan. Three factors impact the finger-stick procedure: the amount of sample

38 THE CLINICAL ADVISOR • MAY 2012 • www.ClinicalAdvisor.com

DIABETES TECHNOLOGY

required by the monitoring system, the lancet device, and the lancet itself.

The size of the blood sample required for monitoring has drastically decreased compared with the amount needed for first-generation monitoring systems. Most current systems require only ≤0.5 µL, approximately the size of the head of a pin. Newer lancet devices minimize motion of the lancet as it penetrates the fingertip. Smaller gauge and shorter lancets help minimize the pain associated with the procedure. Most patients just use the brand of lancets and lancing device that come in the kit with the monitor. However, these lancets may not be optimal for that patient. Test strips are expensive, but a new lancet device is a one-time only cost (typically $20-$30), and even the smallest lancet, the Tiniboy (Health Innovation Ideas, Claremont, Calif.), is only $13 for a box of 100, so patients should use the ones that suit them best. Some patients fail to use a new lancet for each finger-stick. Aside from the potential for infection, reusing a lancet dulls it and increases pain over time. If your patient reports problems with self-monitoring, troubleshooting each of these factors may be worthwhile, as it will allow you to recommend changes in the patient’s monitoring system.

improved patient care, point-of-care testing eliminates a trip to the laboratory for the patient and saves the time the office staff might spend tracking down a missing result. Finally, if patients must pay out of pocket for laboratory services, the point-of-care test is more affordable.

Point-of-care hemoglobin A1c testing

Insulin pens

The American Diabetes Association (ADA) and other expert groups recommend measuring hemoglobin A1c (HbA1c) in every diabetic patient at least twice yearly. Patients whose glycemic control is poor (HbA1c >6.5%-7%) should have an HbA1c determination every three months.8 Since HbA1c provides a measure of overall glycemic control, a current result can improve clinical decision making. Consider a patient who is in the clinic and reports that while his blood glucose results are usually within his target range, sometimes they are a little high. Would you make a different management decision if you knew the HbA1c was 6.8% that day vs. 7.8%?

You probably would. This is the real benefit of point-of-care HbA1c testing: It helps make every visit more productive.9,10 Point-of-care HbA1c tests take five to 10 minutes, including the time for the finger stick. If diabetic patients are identified ahead of time, staff members can collect the sample during the intake process and the provider can start the visit and have the result in time for management decisions.

Point-of-care HbA1c testing has been granted a waiver under the Clinical Laboratory Improvement Amendment.

The HbA1c machine costs about $3,000, and the disposable cartridge for each sample costs approximately $12. The charge code for a point-of-care HbA1c test is 83036, and reimbursement for each test ranges from $13 to $20. In addition to

Patients who take only one or two daily injections (e.g., basal insulin) may not benefit greatly from using a pen rather than a syringe and vial. However, patients who take multiple daily insulin injections almost certainly inject while away from home. For these individuals, insulin pens can dramatically improve acceptance of—and adherence to—the treatment regimen. Although several insulin pens are reusable, with separate insulin cartridges, most are now prefilled and disposable.

To use a pen, a special needle is screwed onto one end of the reservoir that contains insulin. The dose is dialed, the needle is inserted into the subcutaneous space, and a button is pushed to complete the injection. Some insurance plans charge higher copayments for pens, while others require prior authorization for coverage. Plans that require prior authorization are typically looking for a medically necessary reason that the patient cannot safely use a syringe to draw insulin out of a vial and inject it. For example, if a patient has a tremor or sensory neuropathy in the fingers, using an insulin vial and syringe and injecting the accurate dose is very difficult, if not impossible. Poor visual acuity may also qualify a patient for insulin pens through the insurance plan.

Plans that require prior authorization for insulin pens usually will not accept improved patient convenience or adherence as a valid reason for the exception. In that situation, a

POLL POSITION

Do you recommend medical apps for smartphones to help your patients manage diabetes?

n=38

26% 61% 13%

Yes No Not yet, but I'd like to learn more

For more polls, visit www.ClinicalAdvisor/polls

40 THE CLINICAL ADVISOR • MAY 2012 • www.ClinicalAdvisor.com

patient may choose to pay out of pocket for a limited supply of insulin pens to use only when away from home and use a vial and syringe for the remainder of the injections.

AT A GLANCE ●

For patients who are having problems with self-monitoring, troubleshooting each of the factors that impact the fingerstick procedure (amount of sample, lancet device, lancet) may allow you to recommend changes.

●

Point-of-care hemoglobin A1c testing helps make every visit more productive.

●

If cost is an issue, patients may choose to pay out of pocket for a limited supply of insulin pens to use only when away from home.

●

Medicare and other third-party payers require proof of insulin deficiency prior to approving coverage of insulin pump therapy.

Syringes and needles

Selection of the appropriate insulin syringe can make a difference in the patient’s acceptance of the treatment regimen.

Insulin syringes now come in three sizes that hold 30, 50, or 100 units of insulin, respectively. Needles come in a wide variety of lengths and gauges. Most patients prefer the short (5- to 8-mm) needle and the finest gauge available (31-32 G). However, the very fine needles bend easily, and this may cause problems for a patient with limited manual dexterity. Syringe size should be determined by the patient’s insulin regimen. For example, patients who take small amounts of a rapid-acting insulin analog several times daily but are given syringes that hold 1 cc (100 units) will have a difficult and potentially stressful experience measuring and taking their insulin. Patients taking basal/bolus insulin may need syringes of two different sizes—a larger size for basal doses and a smaller size for bolus doses.

Insulin pumps

Many clinicians have been waiting decades for the holy grail of diabetes treatment: a closed-loop insulin delivery system, or artificial endocrine pancreas, that would sense the blood glucose level and automatically infuse the correct amount of insulin at all times. Unfortunately, a closed-loop system remains on the horizon, but current insulin pumps offer many advantages to some patients. When discussing pump therapy, begin by determining what the patient understands about the benefits and limitations of insulin pumps. Patients who are underinformed may assume that currently available pumps are closed-loop systems. When they learn that this is not yet the case, some may no longer be interested.

An insulin pump is a different and sometimes (but not always) better option for insulin delivery. Insulin pumps deliver tiny amounts of insulin continuously, typically a fraction of a unit per hour (the basal rate). Patients are taught to program the pump for larger doses to cover the amount of carbohydrates in meals or to correct hyperglycemia (a

PEER PERSPECTIVES

bolus dose). Specific features of insulin pumps vary among manufacturers. A detailed description of each is beyond the scope of this article, but they all share basic functions.

Most insulin pumps are about the size of a pager and house a disposable syringe (insulin reservoir) connected to a length of tubing. The pump is connected to the patient via a cannula on the end of the tubing, which is inserted into the subcutaneous space, usually in the abdomen. The insertion is similar to that of an IV cannula; the entire unit consists of a sharp needle surrounded by a plastic cannula. The unit is inserted intact, and the needle is removed, leaving the soft cannula in place. The cannula is taped down and remains in place for two to three days, after which it must be changed.

The OmniPod (Insulet Corp, Bedford, Mass.) insulin pump is the exception; it requires no tubing.

Because insulin is delivered continuously, there is no need for long-acting insulin. A bolus dose must work quickly, either to cover a meal or to correct hyperglycemia. Only rapid-acting insulin analogs are typically used in pump therapy. Three different rapid-acting insulin analogs are currently approved by the FDA for use in pumps: Insulin lispro (Humalog), insulin aspart (NovoLog), and insulin glulisine (Apidra). Although they have slightly different pharmacokinetics, all are effective and appropriate choices for pump therapy.

Continues on page 42

“This article hits on all the technological advances available in the management of diabetes and gives valuable tips on using them efficiently. I found it to be a wonderful reference from the perspective of both the patient and the provider.”

Eve Roelker, NP, Tucson, Ariz. (via ClinicalAdvisor.com)

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MAY 2012 41

DIABETES TECHNOLOGY

Patients beginning pump therapy are required to complete a rigorous training program that is arranged for and provided by the manufacturer. Training sessions are typically conducted by certified diabetes educators with advanced training in pump therapy.

Although insulin pumps are usually thought of as a treatment for type 1 diabetes, many patients with type 2 diabetes may also benefit. Because type 2 diabetes is a progressive disease, pancreatic beta-cell function wanes over time.

Patients who have had type 2 diabetes for a long time may be insulin-deficient, like their type 1 counterparts. In addition, patients with type 2 diabetes who require multiple daily injections for glycemic control may be insulin-deficient.

Medicare and other third-party payers require proof of insulin deficiency prior to approving coverage of insulinpump therapy. Deficiency is determined by measuring the concentration of insulin-connecting peptide, or C-peptide, in the blood. Insulin is created from proinsulin by the cleavage of a 31-amino acid peptide (Figure 1). The peptide gets its name because it once “connected” the two chains of the proinsulin molecule. Insulin and C-peptide are localized within the same secretory vesicle in the beta cell and are secreted together into the circulation. Measurement of the plasma C-peptide concentration is therefore an indirect measure of endogenous insulin production and secretion.

For a detailed explanation of insulin-pump therapy, attend Medtronic MiniMed’s virtual pump school (pumpschool. minimed.com/index.tpl). Registration is required but is free. This is also an excellent tool to recommend to patients, either to help them make a decision regarding pump therapy or to provide a head start on training if they have already decided to start using a pump.

Continuous glucose monitors

Continuous glucose monitoring (CGM) can improve glycemic control for people with erratic swings in blood glucose levels.11-16 Two different strategies for CGM are available: professional and personal. Professional CGM equipment is owned by the health-care provider and is typically worn by the patient for three to five days. With this system, the patient is unaware of the CGM results until the data are downloaded and analyzed by the provider. Personal CGM devices are owned by the patient, who has access to continuous results,

MAKING CONTACT

Follow us on Twitter @ClinicalAdvisor

CLINICAL SLIDESHOW Nearly one-third of patients with diabetes have some type of dermatologic manifestation. To learn more, visit ClinicalAdvisor.com/CutaneousDiabetesSlideshow.

allowing the individual to make adjustments to prevent and treat hyperglycemia and hypoglycemia.17 Most CGM devices can be programmed for a high and a low threshold, outside of which an alarm will sound to alert the patient of the need for treatment or adjustment. These systems are particularly useful for patients with hypoglycemia unawareness—that is, those who lack early warning signs of hypoglycemia and sometimes experience cognitive impairment as the first warning of decreased blood glucose.17-19 CGM devices have also been used successfully in a pediatric population.20 Overall, however, studies of the ability of CGM devices to improve overall glycemic control have not been consistently positive.18 Candidates for CGM devices should be chosen carefully. The American Association of Clinical Endocrinologists recommends that candidates for personal CGM include: • Patients with hypoglycemia unawareness or frequent hypoglycemia • Patients with excess glycemic variability • Patients who require HbA1c-lowering and would be at extreme risk if they were to become hypoglycemic • Women who are planning to become pregnant or who are already pregnant.17 The full benefit of CGM is attainable only when it is used under the supervision of a provider or a diabetes educator who is knowledgeable, experienced, and willing to take the necessary time to analyze and interpret the copious amounts of data available from these systems.

Diabetes education

Diabetes education is critically important in the care of patients with diabetes. Partnering with a diabetes educator or a diabetes education program is an excellent strategy for improving patient care. As reviewed here, many technological options

Like us on Facebook facebook.com/TheClinicalAdvisor

42 THE CLINICAL ADVISOR • MAY 2012 • www.ClinicalAdvisor.com

Visit us on the web ClinicalAdvisor.com

Go mobile with us mobile.ClinicalAdvisor.com

are available, and dedicated time and effort on the part of the educator are required to develop expertise in the selection and use of the appropriate tools for each patient. Diabetes educators stay abreast of current trends and can often co-manage patients when given the opportunity. For example, an educator may use a data-management system to help a patient optimize the blood glucose testing schedule and better evaluate a particular treatment regimen. In addition, the educator may recommend a change in treatment regimen that may help improve adherence, reduce adverse effects, or improve glycemic control. Some diabetes educators are also advanced-practice clinicians with prescribing privileges, so providers should determine, during the referral process, who will be making treatment changes.

To find a diabetes educator near you, visit the website of the American Association of Diabetes Educators (www.diabeteseducator.org), and click on “Find a Diabetes Educator.”

To find a diabetes education program that has been certified by the ADA, visit the ADA website (professional.diabetes. org/erp_zip_search.aspx). ■

8. American Diabetes Association. Standards of medical care in diabetes —2010. Diabetes Care. 2010;33(Suppl 1):S11-S61.

9. Kennedy L, Herman WH, Strange P, et al. Impact of active versus usual algorithmic titration of basal insulin and point-of-care versus laboratory measurement of HbA1c on glycemic control in patients with type 2 diabetes: the Glycemic Optimization with Algorithms and Labs at Point of Care (GOAL A1c) trial. Diabetes Care. 2006;29:1-8. Available at care.diabetesjournals.org/content/29/1/1.long.

10. Miller CD, Barnes CS, Phillips LS, et al. Rapid A1c availability improves clinical decision-making in an urban primary care clinic. Diabetes Care. 2003; 26:1158-1163. Available at care.diabetesjournals.org/content/26/4/1158.long.

11. Bailey TS, Zisser HC, Garg SK. Reduction in hemoglobin A1C with realtime continuous glucose monitoring: results from a 12-week observational study. Diabetes Technol Ther. 2007;9:203-210.

12. Bode B, Gross K, Rikalo N, et al. Alarms based on real-time sensor glucose values alert patients to hypo- and hyperglycemia: The Guardian Continuous Monitoring System. Diabetes Technol Ther. 2004;6:105-113.

13. Bode BW, Gross TM, Thornton KR, Mastrototaro JJ. Continuous glucose monitoring used to adjust diabetes therapy improves glycosylated hemoglobin: a pilot study. Diabetes Res Clin Pract. 1999;46:183-190.

Dr. Dokken is an assistant professor of medicine in the Section of Endocrinology and a principal investigator in the Diabetes Research Program, University of Arizona, Tucson.

14. Deiss D, Bolinder J, Riveline JP, et al. Improved glycemic control in poorly controlled patients with type 1 diabetes using real-time continuous glucose monitoring. Diabetes Care. 2006;29:2730-2732. Available at care. diabetesjournals.org/content/29/12/2730.long.

References

15. Neithercott T. Continuous glucose monitors. Diabetes Forecast.

1. Bunker K, Toves K. Blood glucose meters. Diabetes Forecast. 2011;64:30-42.

2011;64:44-46.

2. Waldron-Lynch F, Dinneen S. Self-monitoring of blood glucose did not

16. Reach G. Continuous glucose monitoring and diabetes health out-

improve glycaemic control in patients with type 2 diabetes not treated

comes: a critical appraisal. Diabetes Technol Ther. 2008;10:69-80.

with insulin. Evid Based Med. 2008;13:7. Available at ebm ebm.bmj.com/

17. Blevins TC, Bode BW, Garg SK, et al. Statement by the American

content/13/1/7.long.

Association of Clinical Endocrinologists Consensus Panel on continuous

3. Guerci B, Drouin P, Grangé V, et al. Self-monitoring of blood glucose

glucose monitoring. Endocr Pract. 2010;16:730-745. Available at aace.meta-

significantly improves metabolic control in patients with type 2 diabe-

press.com/content/dn0g3p34540303q5/fulltext.pdf.

tes mellitus: the Auto-Surveillance Intervention Active (ASIA) study.

18. Chico A, Vidal-Ríos P, Subirà M, Novials A. The continuous glucose

Diabetes Metab. 2003;29:587-594. Available at www.em-consulte.com/

monitoring system is useful for detecting unrecognized hypoglycemias in

article/80262.

patients with type 1 and type 2 diabetes but is not better than frequent

4. Harris MI; National Health and Nutrition Examination Survey.

capillary glucose measurements for improving metabolic control. Diabetes

Frequency of blood glucose monitoring in relation to glycemic control in

Care. 2003;26:1153-1157. Available at care.diabetesjournals.org/con-

patients with type 2 diabetes. Diabetes Care. 2001;24:979-982. Available at

tent/26/4/1153.long.

care.diabetesjournals.org/content/24/6/979.long.

19. Kubiak T, Hermanns N, Schreckling HJ, et al. Assessment of hypo-

5. Karter AJ, Ackerson LM, Darbinian JA, et al. Self-monitoring of blood

glycaemia awareness using continuous glucose monitoring. Diabet Med.

glucose levels and glycemic control: the Northern California Kaiser

2004;21:487-490.

Permanente Diabetes registry. Am J Med. 2001;111:1-9.

20. Kaufman FR, Gibson LC, Halvorson M, et al. A pilot study of the

6. McAndrew L, Schneider SH, Burns E, Leventhal H. Does patient blood glu-

continuous glucose monitoring system: clinical decisions and glyce-

cose monitoring improve diabetes control? Diabetes Educ. 2007;33:991-1011.

mic control after its use in pediatric type 1 diabetic subjects. Diabetes

7. Murata GH, Shah JH, Hoffman RM, et al. Intensified blood glucose

Care. 2001;24:2030-2034.Available at care.diabetesjournals.org/con-

monitoring improves glycemic control in stable, insulin-treated veterans

tent/24/12/2030.long.

with type 2 diabetes. Diabetes Care. 2003;26:1759-1763. Available at care. diabetesjournals.org/content/26/6/1759.long.

All electronic documents accessed April 15, 2012.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MAY 2012 43

Advisor Forum These are letters from practitioners around the country who want to share their clinical problems and successes, observations, and pearls with their colleagues. Responding consultants are identified below. We invite you to participate.

Inside the Forum M AY 2 0 1 2

Consultations Secondary malignancy following breast and uterine cancer . . . . . . . . .44 Drug-testing a teenager without permission. . . . . . . . . . . . . . . . . . . .44 Contraception for women older than age 50 years . . . . . . . . . . . . . . .45 Aspirin and clopidogrel after coronary bypass surgery . . . . . . . . . . .45

Clinical Pearls Keeping a bleeding child calm . . . . . .46 Eye-drop application tips . . . . . . . . . . . . 46 Illustrating coronary anatomy . . . . . . .46

Send us your letters with questions and comments to: Advisor Forum, The Clinical Advisor, 114 West 26th Street, 4th Floor, New York, NY 10001.

You may also fax (646) 638-6117, or contact us by e-mail at letters@ clinicaladvisor.com.

If you are writing in response to a published letter, please indicate so by including the number in parentheses at the end of each item. Letters are edited for length and clarity. The Clinical Advisor’s policy is to print the author’s name with the letter.

No anonymous contributions will be accepted.

CONSULTATIONS SECONDARY MALIGNANCY FOLLOWING BREAST AND UTERINE CANCER For the past eight months, a woman aged 78 years has experienced anterior thigh pain that intensifies when she coughs. She has a history of uterine and breast cancers. X-ray reveals arthritis of the hip and an old bone infarct of the thigh at pain site. Could this be osteosarcoma?—LILLIAN RIDDICK, ANPC, PhD, Bridgeport, Conn.

Breast cancer and uterine cancer do not typically cluster with sarcoma.

If the woman received radiation therapy, the risk for such secondary malignancy as sarcoma would be confined to the radiation field. If you are concerned about sarcoma, an MRI is the best choice. Re-evaluation with an oncologist will determine if there is any recurrence.—Deborah L. Cross, MPH, CRNP, ANP-BC (163-1)

DRUG-TESTING A TEENAGER WITHOUT PERMISSION I occasionally get requests from parents to drug-test their teenager at his or her annual physical without the child’s knowledge or consent. The parent usually advises, “Just say you’re doing a cholesterol check.” I tell the parent that this is not possible, and we discuss ways to initiate a conversation regarding drug use. Drug-testing teenagers under false

OUR CONSULTANTS

Rebecca H. Bryan, APRN, CNP,

Eileen Campbell, MSN, CRNP,

Philip R. Cohen, MD,

is a lecturer in the Family Health NP Program, University of Pennsylvania School of Nursing, Philadelphia.

is associate program director, Family Health NP Program, University of Pennsylvania School of Nursing, Philadelphia.

is clinical associate professor of dermatology, University of Texas Medical Center, Houston.

44 THE CLINICAL ADVISOR • MAY 2012 • www.ClinicalAdvisor.com

Deborah L. Cross, MPH, CRNP, ANP-BC, is associate program

director, Gerontology NP program, University of Pennsylvania School of Nursing, Philadelphia.

Maria Kidner, DNP, FNP-C,

is a nurse practitioner with Cheyenne Cardiology Associates in Cheyenne, Wyo.

pretenses is unethical and against the policy of my practice setting, but I also believe it is illegal. Am I correct?—BETSY GROTH, APRN, Essex, Ct. Drug-testing is legal and can be of diagnostic and therapeutic value in the context of treatment in individuals with substance-abuse problems or those in emergency situations. However, involuntary drug-testing is not recommended by the American Academy of Pediatrics (AAP) in a person considered competent, such as an older adolescent (Pediatrics. 2007;119:627-630; available at pediatrics .aappublications.org/content/119/3/627.long, accessed April 15, 2012). Parental permission is not sufficient for involuntary screening.

This is not to say that health-care providers should not screen for drug use and abuse. The AAP recommends the use of a validated screening tool like the CRAFFT, brief office interventions, and appropriate referrals (Pediatrics. 2011;128:e1330-e1340; available at pediatrics.aappublications.org/content/128/5/e1330.long, accessed April 15, 2012).—Julee B. Waldrop, DNP (163-2)

CONTRACEPTION FOR WOMEN OLDER THAN AGE 50 YEARS Is there a preferred contraceptive method for a woman older than age 50 years still having her period?—CONNIE KELLY, FNP, Franklin, N.Y. The risk of a pregnancy is extremely low in such a woman.

Nevertheless, birth control should be continued until menopause is confirmed (clinically defined as one year of no menses in a woman of menopausal age). A 50-year-old woman who is otherwise healthy should be counseled on all birth-control options, but I would guide her away from such invasive and long-term methods as an intrauterine device or Essure, as she is likely on the verge of menopause. If she is interested in oral contraception (OC), there

are many low-dose options, including a pill containing only 10 μg of ethinyl estradiol (although there is no contraindication to using a 20 μg pill in this population).

Since OCs can mask menopause, the question is when to stop taking the pill. Some clinicians wait for menopausal symptoms to appear during the hormone-free week, after which the woman can stop OCs and see how her cycle responds. Another option is to periodically check follicle-stimulating hormone (FSH) level. If her FSH is >20 mIU/mL, most clinicians would feel confident taking her off OCs, as the risk of pregnancy is virtually nil.—Mary Newberry, CNM, MSN (163-3)

ASPIRIN AND CLOPIDOGREL AFTER CORONARY BYPASS SURGERY What are the current evidence-based recommendations for aspirin and clopidogrel (Plavix) use following coronary artery bypass graft (CABG) surgery (both on- and off-pump procedures)? If possible, please include medication dosages and length of treatment.—MERIANNE LORENZEN, PA-C, Bryn Mawr, Pa. Such studies as the CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events) (Circulation. 2004;110:12021208; available at circ.ahajournals.org/content/110/10/1202. long, accessed April 15, 2012), CASCADE (Clopidogrel After Surgery for Coronary Artery DiseasE) (Curr Control Trials Cardiovasc Med. 2005;6:15; available at www.ncbi.nlm.nih .gov/pmc/articles/PMC1282584/, accessed April 15, 2012), and various meta-analyses of the efficacy of clopidogrel and aspirin have addressed this topic. Multivariate analysis states that beyond 30 days, there is no significant difference in the end point with the use of aspirin vs. aspirin and clopidogrel. The CURE study subgroup analysis showed no benefit of clopidogrel following CABG. The

Debra August King, PHD, PA,

Mary Newberry, CNM, MSN

Claire O’Connell, MPH, PA-C,

Sherril Sego, FNP-C, DNP,

Julee B.Waldrop, DNP,

is senior physician assistant of the Department of Cardiothoracic Surgery, Lenox Hill Hospital, New York City.

provides well-woman gynecologic care as a midwife with Prima Medical Group, Greenbrae, Calif.

teaches in the PA Program at the New Jersey Medical School and Rutgers University, Piscataway, N.J.

is a primary-care nurse practitioner at the Department of Veterans Affairs Medical Center in Kansas City, Mo.

teaches at the University of North Carolina School of Nursing in Chapel Hill and practices pediatrics at UNC Hospitals.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MAY 2012 45

Transforming the Lives of Service Members with TBI. Clinical Care. Education. Research. That’s DVBIC. Mild TBI Pocket Guide - Clinical tool for mTBI assessment and treatment

Patient Handouts - Headache/Neck Pain - Improving Memory - Mood Changes - Healthy Sleep - Dizziness

iPhone

Android

Co-occurring Conditions Toolkit: Mild TBI and Psychological Health - Unique approaches for treating TBI with PTSD, depression, chronic pain, headaches and substance abuse Android

To request copies, email info@DVBIC.org

DVBIC.ORG

iPhone

Visit us at the AAPA and AANP conferences

BRAINLINEMILITARY.ORG

CASCADE study compared aspirin alone with a combination of aspirin and clopidogrel and showed no significant reduction in the process of saphenous vein intimal hyperplasia at one year. A retrospective analysis involving more than 15,000 patients concluded that the relative effect of combined treatment did not differ between on- and offpump ( J Thorac Cardiovasc Surg. 2009;138:1377-1384). Other studies have concluded that there is no significant difference between clopidogrel alone compared to aspirin with clopidogrel in (saphenous) graft patency (Ann Thorac Surg. 2009; 88: 59-62).

It has been recommended to use aspirin indefinitely and clopidogrel for a minimum of one month to one year following CABG. However, each patient should be evaluated independently. The platelet count will dictate the therapy, as will the survival rate, coronary stent placement, risk of GI bleed, and a history of recent myocardial infarction. Aspirin dosage (81 mg vs. 325 mg) has not been clearly established, so assess each patient separately.—Debra King, PhD, PA (163-4)

CLINICAL PEARLS KEEPING A BLEEDING CHILD CALM Keep dark washcloths in your first-aid kit for treating childhood cuts and bleeding injuries. The dark color prevents the child (and his or her parents and teammates or classmates)

INFO@DVBIC.ORG

from being startled by the amount of blood. You will be able to get the injured child to the sidelines, camp infirmary, or emergency department before symptoms of shock develop.—E. ROSELLEN DEDLOW, PNP, Gainesville, Fla. (163-5)

EYE-DROP APPLICATION TIPS I instruct patients to warm their eye-drop bottle by holding them for five minutes before use. This reduces thermal shock to the eyes and makes the drops much more easily tolerated. I also tell these patients not to blink for a minute or two after applying the drops and to keep their eyes closed and roll them around under the lids. This helps distribute the medicine and avoids washing it out with tears generated by blinking.—THOMAS URSCHEL, RPAC, Clarendon, N.Y. (163-6)

ILLUSTRATING CORONARY ANATOMY When explaining coronary anatomy to a patient, I compare the coronary arteries to the roots that feed a tree. By way of illustration, I wrap the fingers of one hand over the fist of the other.—JOAN M. LACEY, ACNP, ANP, AACC, Greenville, S.C. (163-7) ■

46 THE CLINICAL ADVISOR • MAY 2012 • www.ClinicalAdvisor.com

LEGAL ADVISOR CASE

A clinician sues after being fired

BY ANN W. LATNER, JD

For more than 10 years, Ms. P, a 40-year-old nurse practitioner, enjoyed a stable and prosperous job in general practice. She had worked her way to a supervisory role at a small practice consisting of one physician, and she was well respected. Two years ago, Ms. P was forced to move on as the physician running the practice retired.

She took a new job at an area nursing home that was associated with a large medical facility.Within a short span of time Ms. P found herself unhappy with the work environment. She was used to being in charge and accustomed to working independently and was irritated at the level of supervision, amount of paperwork, and general work environment. As a result, there was a good deal of conflict between Ms. P and her direct supervisor, Ms.S, as well as with other coworkers.

During the course of her employment, Ms. P was reprimanded on several occasions. First, she was pulled aside when she accidently gave a patient medication that had been prescribed to another patient. Ms. P defended herself by saying that the physician orders here were unclear. The second instance occurred when a fellow employee reported

© PUNCHSTOCK.COM

Discriminatory action is raised against an unsuspecting supervisor who was just doing her job.

Concerned that the physician was not attentive enough, the nurse practitioner ordered the transfer herself.

Ms. P for having caused undue trauma to a patient during a catheter removal. Ms. P felt that she was being treated unfairly, and complained to Ms. S, the nursing supervisor, about the nurse who had reported the incident. The supervisor dismissed Ms. P’s complaints.

Ms. P also complained about another coworker who she felt was rude and condescending to her.

On several occasions she reported this nurse’s actions or comments, but Ms. S did not follow up nor discipline the other nurse. Ms. P wrote a letter to Ms. S complaining about her failure to respond to the issues with the other employee, but Ms. S still did not act.

The final incident between the two happened after Ms. P wrote in a patient’s file that the doctor had ordered that the patient be transferred to the hospital. This was not, in fact, the case. Ms. P had been extremely concerned about the patient, and Cases presented are based on actual occurrences.

Names of participants and details have been changed.

Cases are informational only; no specific legal advice is intended. Persons pictured are not the actual individuals mentioned in the article.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MAY 2012 51

LEGAL ADVISOR

Title VII of the Civil Rights Act of 1964 prohibits employers from making decisions based on “protected” traits.

Ms. P fi led a lawsuit against the nursing home, alleging race discrimination in violation of the Civil Rights Act. The discovery process began and the nursing home produced its records, which included Ms. P’s letter complaining that Ms. S was not paying attention to her complaints about her coworker. The disciplinary records regarding the three events for which Ms. P was reprimanded were also brought forward. Depositions began and each side had the opportunity to question potential witnesses.

After the discovery process, but prior to trial, the nursing home attorneys fi led a motion to dismiss the lawsuit, claiming that no discrimination had taken place and that Ms. P had been fired for cause. The court looked at all three incidents in order to determine whether any racial animus had been shown. In the first incident, the court held that giving a patient the wrong medication was a clear violation of policy and procedure. In the second incident, involving the catheter removal, the court found no evidence of any racial bias regarding this incident. The final issue—writing orders for hospital transfer in a patient’s chart—was also a clear violation of nursing home policy, the court said. The resulting action, the termination of Ms. P, contained no overtones of racial animus, the court found.

Finally, the court examined Ms. P’s claims that her supervisor had ignored her repeated complaints about a black coworker. The court pointed out that Ms. P claimed that had a different nurse (and she named a white one) complained, those complaints would have been heeded. Because of this, said the court, it was clear that Ms. P did not actually believe

that Ms. S’s failure to respond was based on race. The court also pointed out that Ms. S had previously initiated disciplinary actions against other black employees, indicating that race was not a motivating factor. The court held that Ms. P failed to demonstrate that her termination was based on her race. The case was dismissed.

Legal background

Title VII of the Civil Rights Act of 1964 prohibits employment discrimination based on race, color, religion, sex, or national origin. In the simplest terms, Title VII prohibits employers from making employment-related decisions when the decision is motivated by a person’s protected trait.

In order to establish a discrimination claim, the employee must show that there was unfair treatment based on protected traits. In Ms. P’s case, her employer had clear and valid reasons for terminating her employment, which had nothing to do with race.

Protecting yourself

Ms. P made several serious errors while working. Giving a patient the wrong medication was certainly grounds for discipline, even if the patient was not injured by the medicine. But the most egregious error that Ms. P made was to write physician orders in a patient’s chart when the physician had not ordered the action. By any standards, this clearly crossed the boundary from “mistake” to “intentional action.”

Ms. P was terminated from her job because of what she did, not because of her race—and her perception that the supervisor was harder on her because she was black was a mischaracterization of the events and a reflection of Ms. P’s unwillingness to take responsibility for her own actions. ■ Ms. Latner, a former criminal defense attorney, is a freelance medical writer in Port Washington, N.Y.

52 THE CLINICAL ADVISOR • MAY 2012 • www.ClinicalAdvisor.com

“He’s a mental-health critic.”

© The New Yorker Collection 2012 from cartoonbank.com. All Rights Reserved.

felt that the physician wasn’t attentive enough and that the patient needed an immediate transfer to the hospital, so she took it upon herself to write in the chart that the physician had been notified and ordered the hospital transfer.

When it was discovered that the physician had not ordered the hospital transfer, Ms. P was terminated from her employment.

Ms. P became convinced that her firing—and her supervisor’s treatment of her—was racially motivated. Ms. P was white, and after ruminating on events she came to the conclusion that Ms. S, who was black, was ignoring her complaints and disciplining her based on her race.

COMMENTARY Mandi Bartlett, RN, BSN, is an oncology nurse in Pittsburgh and is graduating this spring as a family nurse practitioner.

Don’t let patients tan their lives away To most teenage girls, nothing goes better with summer, sun, and fl ip-flops than the perfect tan.

Perhaps this is why so many girls visit tanning salons to work on achieving that bronzed skin.

My mother was one of those sun-worshippers, and I always envied her deep tans. As I got older, she would let me come along to the tanning bed with her. At first it was just before special occasions such as a wedding or the prom, and then it became every April or May, “to get ready for summer.”

Everyone has heard at one time or another that too much sun exposure can be unhealthy—but no one ever warned my mother or me just how dangerous it could be.

At the age of 22, my worst fear had come true. But my melanoma was caught early, and I am one of the few lucky ones.

I graduated from college and began working as an inpatient oncology nurse. I will never forget when I saw my first patient die from stage IV melanoma. I vowed on that day that I would never lie down again in a tanning bed.

But even at the age of 22, it was still too late.

My boyfriend pointed out a mole on my hip that he noticed was bigger than it used to be, oddly shaped, and changing colors. I called my dermatologist to schedule a biopsy. Two days after Christmas, in 2010, he called me to tell me the results were in: I had melanoma.

My worst fear had come true. The next few months were a whirlwind of surgeries, PET scans, and trips to the oncologist. Fortunately, my melanoma was caught very early, and I am ecstatic to say that I am cancer-free. I am one of the few lucky ones.

Many states now require parental permission for teens to use tanning beds. But do parents really understand what they are consenting to?

Girls following in my footsteps will come up with 100 reasons for their parents to grant permission, but we as health-care providers need to give parents one really big reason to say no.

Tanning beds emit two different types of ultraviolet (UV) rays: UVA and UVB. The UVB rays are responsible for more superficial damage, such as sunburns. UVA rays are what cause deeper damage to the skin. These beds emit 10 to 15 times more UVA than the sun.

72 THE CLINICAL ADVISOR • MAY 2012 • www.ClinicalAdvisor.com

UV rays have been found to be so destructive that the International Agency for Research on Cancer has labeled them “carcinogenic to humans,” which puts them in the same category as tobacco, mustard gas, and plutonium (monographs.iarc.fr/ENG/Classification/index. php, accessed April 15, 2012). After recurrent damage, the cells in the body start to mutate, turning into cancer.

The three most common skin cancers are basal cell, squamous cell, and melanoma. Melanoma accounts for only 5% of all skin cancers, but it is the most dangerous.

Be sure your patients understand that cancer that grows on the skin is no less devastating than cancer that grows in the lungs, bones, or brain.

One person dies every 62 minutes from melanoma, which is the second most common cancer in females aged 15 to 29 years (www.skincancer. org/skin-cancer-information/skin-cancer-facts, accessed April 15, 2012). Tanning increases a girl’s risk of melanoma by 75% (www.cdc.gov /cancer/skin/basic_info/indoor_tanning.htm, accessed April 15, 2012).

We tell our kids that smoking is bad, that alcohol is dangerous…but we fail to tell them about the dangers of tanning beds. Health professionals need to help parents help their teenagers understand the long-term risks of tanning beds so these youths can ultimately save their beautiful skin—and their lives. ■

Evolving anticoagulation in patients with NVAF, including those at increased stroke risk...

HELP INTERCEPT STROKE RISK

...combining proven protection, a demonstrated safety profile, and convenient once-daily dosing XARELTO® (rivaroxaban) is indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (NVAF).

There are limited data on the relative effectiveness of XARELTO® and warfarin in reducing the risk of stroke and systemic embolism when warfarin therapy is well controlled.

IMPORTANT SAFETY INFORMATION WARNING A. DISCONTINUING XARELTO® IN PATIENTS WITH NONVALVULAR ATRIAL FIBRILLATION Discontinuing XARELTO® places patients at an increased risk of thrombotic events. An increased rate of stroke was observed following XARELTO® discontinuation in clinical trials in atrial fibrillation patients. If anticoagulation with XARELTO® must be discontinued for a reason other than pathological bleeding, consider administering another anticoagulant.

Please see additional Important Safety Information and brief summary of Prescribing Information, including Boxed WARNINGS, on following pages.

Once-daily XARELTO® delivers...

Proven protection Effective reduction in risk of stroke and non-CNS systemic embolism* Results achieved in NVAF patients with multiple comorbidities reflecting increased risk of stroke

A demonstrated safety profile Comparable major bleed rates† versus warfarin: rivaroxaban 3.6, warfarin 3.5 per 100 patient-years In bleeding categories of great concern, such as bleeding into a critical organ‡ and fatal bleeding, fewer events were observed with XARELTO®§ In the categories of transfusions and gastrointestinal bleed, more events were observed with XARELTO®§

Convenient once-daily dosing and administration Oral 20-mg fixed dose taken once daily with the evening meal (15 mg for patients with CrCl 15 mL/min to 50 mL/min) No routine monitoring of INR or other coagulation parameters is required1 If a dose of XARELTO® is not taken at the scheduled time, administer the dose as soon as possible on the same day

E vent rates per 100 patient-years, rivaroxaban versus warfarin: critical-organ bleeding 0.8 versus 1.2; fatal bleeding 0.2 versus 0.5; bleeding resulting in transfusion of ≥2 units of whole blood or packed red blood cells 1.7 versus 1.3; gastrointestinal bleeding 2.0 versus 1.2.

§

IMPORTANT SAFETY INFORMATION (cont’d) Warning (cont’d) B. SPINAL/EPIDURAL HEMATOMA Epidural or spinal hematomas have occurred in patients treated with XARELTO® who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include: Use of indwelling epidural catheters Concomitant use of other drugs that affect hemostasis, such as nonsteroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants, see Drug Interactions A history of traumatic or repeated epidural or spinal punctures A history of spinal deformity or spinal surgery Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary.

Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis.

CONTRAINDICATIONS Active pathological bleeding and severe hypersensitivity reaction to XARELTO®.

WARNINGS AND PRECAUTIONS Increased Risk of Stroke After Discontinuation in Nonvalvular Atrial Fibrillation: Discontinuing XARELTO®, in the absence of adequate alternative

anticoagulation, increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from XARELTO® to warfarin in clinical trials in atrial fibrillation patients. If XARELTO® must be discontinued for a reason other than pathological bleeding, consider administering another anticoagulant.

Risk of Bleeding: XARELTO® increases the risk of bleeding and can cause serious or fatal bleeding. In deciding whether to prescribe XARELTO® to patients at increased risk of bleeding, the risk of thrombotic events should be weighed against the risk of bleeding.

Promptly evaluate any signs or symptoms of blood loss. Discontinue XARELTO® in patients with active pathological hemorrhage.

• A specific antidote for rivaroxaban is not available.

Because of high plasma protein binding, rivaroxaban is not expected to be dialyzable. Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban. There is no experience with antifibrinolytic agents (tranexamic acid, aminocaproic acid) in individuals receiving rivaroxaban. There is neither scientific rationale for benefit nor experience with systemic hemostatics (desmopressin and aprotinin) in individuals receiving rivaroxaban. Use of procoagulant reversal agents such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate (APCC), or recombinant factor VIIa (rFVIIa) may be considered, but has not been evaluated in clinical trials.

• Concomitant use of drugs affecting hemostasis increases the risk of bleeding. These include aspirin, P2Y12 platelet inhibitors, other antithrombotic agents, fibrinolytic therapy, and NSAIDs.

Please see additional Important Safety Information and brief summary of Prescribing Information, including Boxed WARNINGS, on following pages.

IMPORTANT SAFETY INFORMATION (cont’d) • Concomitant use of drugs that are combined P-gp and CYP3A4 inhibitors (eg, ketoconazole and ritonavir) increases rivaroxaban exposure and may increase bleeding risk.

Spinal/Epidural Anesthesia or Puncture: When neuraxial anesthesia (spinal/epidural anesthesia) or spinal puncture is employed, patients treated with anticoagulant agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma, which can result in long-term or permanent paralysis.

An epidural catheter should not be removed earlier than 18 hours after the last administration of XARELTO®. The next XARELTO® dose is not to be administered earlier than 6 hours after the removal of the catheter. Delay the administration of XARELTO® for 24 hours if traumatic puncture occurs.

Risk of Pregnancy-Related Hemorrhage: Use with caution in pregnant women and only if the potential benefit justifies the potential risk to the mother and fetus. The anticoagulant effect of XARELTO® cannot be monitored with standard laboratory testing and is not readily reversed. Promptly evaluate any signs or symptoms suggesting blood loss (eg, a drop in

hemoglobin and/or hematocrit, hypotension, or fetal distress). Pregnancy Category C Severe Hypersensitivity Reactions: There were postmarketing cases of anaphylaxis in patients treated with XARELTO® to reduce the risk of deep vein thrombosis (DVT). Patients who have a history of a severe hypersensitivity reaction to XARELTO® should not receive XARELTO®.

DRUG INTERACTIONS Drugs That Inhibit CYP3A4 Enzymes and Drug Transport Systems: Avoid concomitant administration of XARELTO® with combined P-gp and strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, lopinavir/ ritonavir, ritonavir, indinavir/ritonavir, and conivaptan), which cause significant increases in rivaroxaban exposure that may increase bleeding risk.

Drugs That Induce CYP3A4 Enzymes and Drug Transport Systems: Avoid concomitant use of XARELTO® with drugs that are combined P-gp and strong CYP3A4 inducers (eg, carbamazepine, phenytoin, rifampin, St. John’s wort) due to decreases in rivaroxaban exposure that may decrease efficacy.

CNS = central nervous system; CrCl = creatinine clearance; INR = international normalized ratio.

*A randomized, phase 3, multicenter, active-controlled, double-blind, double-dummy,

event-driven study in more than 14,000 patients with NVAF. Patients received XARELTO® 20 mg once daily (15 mg once daily in patients with CrCl 30 mL/min-50 mL/min) or dose-adjusted warfarin titrated to an INR range of 2.0-3.0.1 † Defined as clinically overt bleeding associated with a decrease in hemoglobin of ≥2 g/dL, transfusion of ≥2 units of packed red blood cells or whole blood, bleeding at a critical site, or with a fatal outcome. Hemorrhagic strokes were counted as both bleeding and efficacy events. Major bleeding rates excluding strokes were 3.3 for XARELTO® and 2.9 for warfarin per 100 patient-years. ‡ The majority of critical-organ bleeding events were intracranial, and also included intraspinal, intraocular, pericardial, intra-articular, intramuscular with compartment syndrome, or retroperitoneal.

Learn more at www.XARELTOhcp.com

Once-daily XARELTO® delivers...

Proven protection Effective reduction in risk of stroke and non-CNS systemic embolism* Results achieved in NVAF patients with multiple comorbidities reflecting increased risk of stroke

A demonstrated safety profile Comparable major bleed rates† versus warfarin: rivaroxaban 3.6, warfarin 3.5 per 100 patient-years In bleeding categories of great concern, such as bleeding into a critical organ‡ and fatal bleeding, fewer events were observed with XARELTO®§ In the categories of transfusions and gastrointestinal bleed, more events were observed with XARELTO®§

Convenient once-daily dosing and administration Oral 20-mg fixed dose taken once daily with the evening meal (15 mg for patients with CrCl 15 mL/min to 50 mL/min) No routine monitoring of INR or other coagulation parameters is required1 If a dose of XARELTO® is not taken at the scheduled time, administer the dose as soon as possible on the same day

E vent rates per 100 patient-years, rivaroxaban versus warfarin: critical-organ bleeding 0.8 versus 1.2; fatal bleeding 0.2 versus 0.5; bleeding resulting in transfusion of ≥2 units of whole blood or packed red blood cells 1.7 versus 1.3; gastrointestinal bleeding 2.0 versus 1.2.

§

IMPORTANT SAFETY INFORMATION (cont’d) Warning (cont’d) B. SPINAL/EPIDURAL HEMATOMA Epidural or spinal hematomas have occurred in patients treated with XARELTO® who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include: Use of indwelling epidural catheters Concomitant use of other drugs that affect hemostasis, such as nonsteroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants, see Drug Interactions A history of traumatic or repeated epidural or spinal punctures A history of spinal deformity or spinal surgery Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary.

Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis.

CONTRAINDICATIONS Active pathological bleeding and severe hypersensitivity reaction to XARELTO®.

WARNINGS AND PRECAUTIONS Increased Risk of Stroke After Discontinuation in Nonvalvular Atrial Fibrillation: Discontinuing XARELTO®, in the absence of adequate alternative

anticoagulation, increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from XARELTO® to warfarin in clinical trials in atrial fibrillation patients. If XARELTO® must be discontinued for a reason other than pathological bleeding, consider administering another anticoagulant.

Risk of Bleeding: XARELTO® increases the risk of bleeding and can cause serious or fatal bleeding. In deciding whether to prescribe XARELTO® to patients at increased risk of bleeding, the risk of thrombotic events should be weighed against the risk of bleeding.

Promptly evaluate any signs or symptoms of blood loss. Discontinue XARELTO® in patients with active pathological hemorrhage.

• A specific antidote for rivaroxaban is not available.

Because of high plasma protein binding, rivaroxaban is not expected to be dialyzable. Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban. There is no experience with antifibrinolytic agents (tranexamic acid, aminocaproic acid) in individuals receiving rivaroxaban. There is neither scientific rationale for benefit nor experience with systemic hemostatics (desmopressin and aprotinin) in individuals receiving rivaroxaban. Use of procoagulant reversal agents such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate (APCC), or recombinant factor VIIa (rFVIIa) may be considered, but has not been evaluated in clinical trials.

• Concomitant use of drugs affecting hemostasis increases the risk of bleeding. These include aspirin, P2Y12 platelet inhibitors, other antithrombotic agents, fibrinolytic therapy, and NSAIDs.

Please see additional Important Safety Information and brief summary of Prescribing Information, including Boxed WARNINGS, on following pages.

IMPORTANT SAFETY INFORMATION (cont’d) • Concomitant use of drugs that are combined P-gp and CYP3A4 inhibitors (eg, ketoconazole and ritonavir) increases rivaroxaban exposure and may increase bleeding risk.

Spinal/Epidural Anesthesia or Puncture: When neuraxial anesthesia (spinal/epidural anesthesia) or spinal puncture is employed, patients treated with anticoagulant agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma, which can result in long-term or permanent paralysis.

An epidural catheter should not be removed earlier than 18 hours after the last administration of XARELTO®. The next XARELTO® dose is not to be administered earlier than 6 hours after the removal of the catheter. Delay the administration of XARELTO® for 24 hours if traumatic puncture occurs.

Risk of Pregnancy-Related Hemorrhage: Use with caution in pregnant women and only if the potential benefit justifies the potential risk to the mother and fetus. The anticoagulant effect of XARELTO® cannot be monitored with standard laboratory testing and is not readily reversed. Promptly evaluate any signs or symptoms suggesting blood loss (eg, a drop in

hemoglobin and/or hematocrit, hypotension, or fetal distress). Pregnancy Category C Severe Hypersensitivity Reactions: There were postmarketing cases of anaphylaxis in patients treated with XARELTO® to reduce the risk of deep vein thrombosis (DVT). Patients who have a history of a severe hypersensitivity reaction to XARELTO® should not receive XARELTO®.

DRUG INTERACTIONS Drugs That Inhibit CYP3A4 Enzymes and Drug Transport Systems: Avoid concomitant administration of XARELTO® with combined P-gp and strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, lopinavir/ ritonavir, ritonavir, indinavir/ritonavir, and conivaptan), which cause significant increases in rivaroxaban exposure that may increase bleeding risk.

Drugs That Induce CYP3A4 Enzymes and Drug Transport Systems: Avoid concomitant use of XARELTO® with drugs that are combined P-gp and strong CYP3A4 inducers (eg, carbamazepine, phenytoin, rifampin, St. John’s wort) due to decreases in rivaroxaban exposure that may decrease efficacy.

CNS = central nervous system; CrCl = creatinine clearance; INR = international normalized ratio.

*A randomized, phase 3, multicenter, active-controlled, double-blind, double-dummy,

event-driven study in more than 14,000 patients with NVAF. Patients received XARELTO® 20 mg once daily (15 mg once daily in patients with CrCl 30 mL/min-50 mL/min) or dose-adjusted warfarin titrated to an INR range of 2.0-3.0.1 † Defined as clinically overt bleeding associated with a decrease in hemoglobin of ≥2 g/dL, transfusion of ≥2 units of packed red blood cells or whole blood, bleeding at a critical site, or with a fatal outcome. Hemorrhagic strokes were counted as both bleeding and efficacy events. Major bleeding rates excluding strokes were 3.3 for XARELTO® and 2.9 for warfarin per 100 patient-years. ‡ The majority of critical-organ bleeding events were intracranial, and also included intraspinal, intraocular, pericardial, intra-articular, intramuscular with compartment syndrome, or retroperitoneal.

Learn more at www.XARELTOhcp.com

IMPORTANT SAFETY INFORMATION (cont’d) NSAIDs/Aspirin: NSAIDs/aspirin are known to increase bleeding; therefore, bleeding risk may be increased when these drugs are used concomitantly with XARELTO®. Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with aspirin, other platelet aggregation inhibitors, or NSAIDs. Clopidogrel: Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with clopidogrel.

Drug-Disease Interactions With Drugs That Inhibit CYP3A4 Enzymes and Drug Transport Systems: Use in patients with CrCl 15 mL/min to 50 mL/min who are receiving concomitant combined P-gp and weak or moderate CYP3A4 inhibitors only if the potential benefit justifies the potential risk.

USE IN SPECIFIC POPULATIONS Nursing Mothers: It is not known if rivaroxaban is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from rivaroxaban, a decision should be made whether to discontinue nursing or discontinue XARELTO®, taking into account the importance of the drug to the mother.

Geriatric Use: In clinical trials the efficacy of XARELTO® in the elderly (65 years or older) was similar to that seen in patients younger than 65 years. Both thrombotic and bleeding event rates were higher in these older patients, but the risk-benefit profile was favorable in all age groups.

Renal Impairment • Patients with renal impairment taking P-gp and weak to moderate CYP3A4 inhibitors may have significant increases in exposure, which may increase bleeding risk.

• For patients with CrCl 15 mL/min to 50 mL/min, the recommended dose of XARELTO® is 15 mg once daily with the evening meal. Avoid use in patients with CrCl <15 mL/min. Periodically assess renal function as clinically indicated (ie, more frequently in

situations in which renal function may decline) and adjust therapy accordingly. Discontinue XARELTO® in patients who develop acute renal failure while on XARELTO®.

Hepatic Impairment: No clinical data are available for patients with severe hepatic impairment. Avoid the use of XARELTO® in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy.

OVERDOSAGE Overdose of XARELTO® may lead to hemorrhage.

A specific antidote for rivaroxaban is not available.

Rivaroxaban systemic exposure is not further increased at single doses >50 mg due to limited absorption.

Discontinue XARELTO® and initiate appropriate therapy if bleeding complications associated with overdosage occur. The use of activated charcoal to reduce absorption in case of XARELTO® overdose may be considered. Due to the high plasma protein binding, rivaroxaban is not expected to be dialyzable.

ADVERSE REACTIONS IN CLINICAL STUDIES Hemorrhage: The most common adverse reactions with XARELTO® were bleeding complications.

The most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 4.3% for XARELTO® versus 3.1% for warfarin. The incidence of discontinuations for nonbleeding adverse events was similar in both treatment groups. In XARELTO®- versus warfarintreated patients, respectively, major bleeding events were 5.6% versus 5.4%.

Other Clinical Trial Experience: In an investigational study of acute medically ill patients being treated with XARELTO® 10-mg tablets, cases of pulmonary hemorrhage and pulmonary hemorrhage with bronchiectasis were observed.

Please see brief summary of Prescribing Information, including Boxed WARNINGS, on following pages.

Learn more at www.XARELTOhcp.com

Reference: 1. Patel MR, Mahaffey KW, Garg J, et al; and the ROCKET AF Steering Committee, for the ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883-891.

XARELTO® is licensed from Bayer HealthCare AG, 51368 Leverkusen, Germany. © Janssen Pharmaceuticals, Inc. 2011 November 2011 02X11227

Janssen Pharmaceuticals, Inc.

Brief Summary of Prescribing Information for XARELTO® (rivaroxaban) XARELTO® (rivaroxaban) tablets, for oral use See package insert for full Prescribing Information WARNINGS: (A) DISCONTINUING XARELTO IN PATIENTS WITH NONVALVULAR ATRIAL FIBRILLATION INCREASES RISK OF STROKE, (B) SPINAL/EPIDURAL HEMATOMA A. DISCONTINUING XARELTO IN PATIENTS WITH NONVALVULAR ATRIAL FIBRILLATION Discontinuing XARELTO places patients at an increased risk of thrombotic events. An increased rate of stroke was observed following XARELTO discontinuation in clinical trials in atrial fibrillation patients. If anticoagulation with XARELTO must be discontinued for a reason other than pathological bleeding, consider administering another anticoagulant [see Dosage and Administration (2.1) in full Prescribing Information, Warnings and Precautions, and Clinical Studies (14.1) in full Prescribing Information].

B. SPINAL/EPIDURAL HEMATOMA Epidural or spinal hematomas have occurred in patients treated with XARELTO who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include: • use of indwelling epidural catheters • concomitant use of other drugs that affect hemostasis, such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants • a history of traumatic or repeated epidural or spinal punctures • a history of spinal deformity or spinal surgery [see Warnings and Precautions and Adverse Reactions].

Monitor patients frequently for signs and symptoms of neurological impairment.

If neurological compromise is noted, urgent treatment is necessary [see Warnings and Precautions].

Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis [see Warnings and Precautions].

INDICATIONS AND USAGE Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular Atrial Fibrillation: XARELTO (rivaroxaban) is indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

There are limited data on the relative effectiveness of XARELTO and warfarin in reducing the risk of stroke and systemic embolism when warfarin therapy is wellcontrolled [see Clinical Studies (14.1) in full Prescribing Information].

CONTRAINDICATIONS XARELTO is contraindicated in patients with: • active pathological bleeding [see Warnings and Precautions] • severe hypersensitivity reaction to XARELTO [see Warnings and Precautions] WARNINGS AND PRECAUTIONS Increased Risk of Stroke after Discontinuation in Nonvalvular Atrial Fibrillation: Discontinuing XARELTO in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from XARELTO to warfarin in clinical trials in atrial fibrillation patients. If XARELTO must be discontinued for a reason other than pathological bleeding, consider administering another anticoagulant [see Dosage and Administration (2.1) and Clinical Studies (14.1) in full Prescribing Information].

Risk of Bleeding: XARELTO increases the risk of bleeding and can cause serious or fatal bleeding. In deciding whether to prescribe XARELTO to patients at increased risk of bleeding, the risk of thrombotic events should be weighed against the risk of bleeding.

Promptly evaluate any signs or symptoms of blood loss. Discontinue XARELTO in patients with active pathological hemorrhage.

A specific antidote for rivaroxaban is not available. Because of high plasma protein binding, rivaroxaban is not expected to be dialyzable [see Clinical Pharmacology (12.3) in full Prescribing Information]. Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban. There is no experience with antifibrinolytic agents (tranexamic acid, aminocaproic acid) in individuals receiving rivaroxaban. There is neither scientific rationale for benefit nor experience with systemic hemostatics (desmopressin and aprotinin) in individuals receiving rivaroxaban. Use of procoagulant reversal agents such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate (APCC), or recombinant factor VIIa (rFVIIa) may be considered, but has not been evaluated in clinical trials.

Concomitant use of drugs affecting hemostasis increases the risk of bleeding. These include aspirin, P2Y12 platelet inhibitors, other antithrombotic agents, fibrinolytic therapy, and non-steroidal anti-inflammatory drugs (NSAIDs) [see Drug Interactions].

Concomitant use of drugs that are combined P-gp and CYP3A4 inhibitors (e.g. ketoconazole and ritonavir) increases rivaroxaban exposure and may increase bleeding risk [see Drug Interactions].

Spinal/Epidural Anesthesia or Puncture: When neuraxial anesthesia (spinal/epidural anesthesia) or spinal puncture is employed, patients treated with anticoagulant agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis [see Boxed Warning].

An epidural catheter should not be removed earlier than 18 hours after the last administration of XARELTO. The next XARELTO dose is not to be administered earlier than 6 hours after the removal of the catheter. If traumatic puncture occurs, the administration of XARELTO is to be delayed for 24 hours.

Risk of Pregnancy Related Hemorrhage: XARELTO should be used with caution in pregnant women and only if the potential benefit justifies the potential risk to the mother and fetus. XARELTO dosing in pregnancy has not been studied.

The anticoagulant effect of XARELTO cannot be monitored with standard laboratory testing nor readily reversed. Promptly evaluate any signs or symptoms suggesting blood loss (e.g., a drop in hemoglobin and/or hematocrit, hypotension, or fetal distress).

XARELTO® (rivaroxaban) tablets Severe Hypersensitivity Reactions: There were postmarketing cases of anaphylaxis in patients treated with XARELTO to reduce the risk of DVT. Patients who have a history of a severe hypersensitivity reaction to XARELTO should not receive XARELTO [see Adverse Reactions].

ADVERSE REACTIONS Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

During clinical development for the approved indications, 11598 patients were exposed to XARELTO. These included 7111 patients who received XARELTO 15 mg or 20 mg orally once daily for a mean of 19 months (5558 for 12 months and 2512 for 24 months) to reduce the risk of stroke and systemic embolism in nonvalvular atrial fibrillation (ROCKET AF) and 4487 patients who received XARELTO 10 mg orally once daily for prophylaxis of DVT following hip or knee replacement surgery (RECORD 1-3).

Hemorrhage: The most common adverse reactions with XARELTO were bleeding complications [see Warnings and Precautions].

Nonvalvular Atrial Fibrillation: In the ROCKET AF trial, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 4.3% for XARELTO vs. 3.1% for warfarin. The incidence of discontinuations for non-bleeding adverse events was similar in both treatment groups.

Table 1 shows the number of patients experiencing various types of bleeding events in the ROCKET AF study.

Table 1: Bleeding Events in ROCKET AF* Parameter

XARELTO N = 7111 n (%) 395 (5.6) 91 (1.3)

Event Rate (per 100 Pt-yrs) 3.6 0.8

Warfarin N = 7125 n (%) 386 (5.4) 133 (1.9)

Event Rate (per 100 Pt-yrs) 3.5 1.2

Major bleeding† Bleeding into a critical organ‡ Fatal bleeding 27 (0.4) 0.2 55 (0.8) 0.5 Bleeding resulting in 183 (2.6) 1.7 149 (2.1) 1.3 transfusion of ≥ 2 units of whole blood or packed red blood cells Gastrointestinal bleeding 221 (3.1) 2.0 140 (2.0) 1.2 * For all sub-types of major bleeding, single events may be represented in more than one row, and individual patients may have more than one event. † Defined as clinically overt bleeding associated with a decrease in hemoglobin of ≥ 2 g/dL, transfusion of ≥ 2 units of packed red blood cells or whole blood, bleeding at a critical site, or with a fatal outcome. Hemorrhagic strokes are counted as both bleeding and efficacy events. Major bleeding rates excluding strokes are 3.3 per 100 Pt-yrs for XARELTO vs. 2.9 per 100 Pt-yrs for warfarin. ‡ The majority of the events were intracranial, and also included intraspinal, intraocular, pericardial, intraarticular, intramuscular with compartment syndrome, or retroperitoneal.

Postmarketing Experience: The following adverse reactions have been identified during post-approval use of rivaroxaban. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and lymphatic system disorders: agranulocytosis Gastrointestinal disorders: retroperitoneal hemorrhage Hepatobiliary disorders: jaundice, cholestasis, cytolytic hepatitis Immune system disorders: hypersensitivity, anaphylactic reaction, anaphylactic shock Nervous system disorders: cerebral hemorrhage, subdural hematoma, epidural hematoma, hemiparesis Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome DRUG INTERACTIONS Rivaroxaban is a substrate of CYP3A4/5, CYP2J2, and the P-gp and ATP-binding cassette G2 (ABCG2) transporters. Inhibitors and inducers of these CYP450 enzymes or transporters (e.g., P-gp) may result in changes in rivaroxaban exposure.

Drugs that Inhibit Cytochrome P450 3A4 Enzymes and Drug Transport Systems: In drug interaction studies evaluating the concomitant use with drugs that are combined P-gp and CYP3A4 inhibitors, increases in rivaroxaban exposure and pharmacodynamic effects (i.e., factor Xa inhibition and PT prolongation) were observed.

Significant increases in rivaroxaban exposure may increase bleeding risk.

• Ketoconazole (combined P-gp and strong CYP3A4 inhibitor): Steady-state rivaroxaban AUC and Cmax increased by 160% and 70%, respectively. Similar increases in pharmacodynamic effects were also observed.

• Ritonavir (combined P-gp and strong CYP3A4 inhibitor): Single-dose rivaroxaban AUC and Cmax increased by 150% and 60%, respectively. Similar increases in pharmacodynamic effects were also observed.

• Clarithromycin (combined P-gp and strong CYP3A4 inhibitor): Single-dose rivaroxaban AUC and Cmax increased by 50% and 40%, respectively. The smaller increases in exposure observed for clarithromycin compared to ketoconazole or ritonavir may be due to the relative difference in P-gp inhibition.

• Erythromycin (combined P-gp and moderate CYP3A4 inhibitor): Both the single-dose rivaroxaban AUC and Cmax increased by 30%.

• Fluconazole (moderate CYP3A4 inhibitor): Single-dose rivaroxaban AUC and Cmax increased by 40% and 30%, respectively.

Avoid concomitant administration of XARELTO with combined P-gp and strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, lopinavir/ritonavir, ritonavir, indinavir/ ritonavir, and conivaptan), which cause significant increases in rivaroxaban exposure that may increase bleeding risk.

IMPORTANT SAFETY INFORMATION (cont’d) NSAIDs/Aspirin: NSAIDs/aspirin are known to increase bleeding; therefore, bleeding risk may be increased when these drugs are used concomitantly with XARELTO®. Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with aspirin, other platelet aggregation inhibitors, or NSAIDs. Clopidogrel: Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with clopidogrel.

Drug-Disease Interactions With Drugs That Inhibit CYP3A4 Enzymes and Drug Transport Systems: Use in patients with CrCl 15 mL/min to 50 mL/min who are receiving concomitant combined P-gp and weak or moderate CYP3A4 inhibitors only if the potential benefit justifies the potential risk.

USE IN SPECIFIC POPULATIONS Nursing Mothers: It is not known if rivaroxaban is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from rivaroxaban, a decision should be made whether to discontinue nursing or discontinue XARELTO®, taking into account the importance of the drug to the mother.

Geriatric Use: In clinical trials the efficacy of XARELTO® in the elderly (65 years or older) was similar to that seen in patients younger than 65 years. Both thrombotic and bleeding event rates were higher in these older patients, but the risk-benefit profile was favorable in all age groups.

Renal Impairment • Patients with renal impairment taking P-gp and weak to moderate CYP3A4 inhibitors may have significant increases in exposure, which may increase bleeding risk.

• For patients with CrCl 15 mL/min to 50 mL/min, the recommended dose of XARELTO® is 15 mg once daily with the evening meal. Avoid use in patients with CrCl <15 mL/min. Periodically assess renal function as clinically indicated (ie, more frequently in

situations in which renal function may decline) and adjust therapy accordingly. Discontinue XARELTO® in patients who develop acute renal failure while on XARELTO®.

Hepatic Impairment: No clinical data are available for patients with severe hepatic impairment. Avoid the use of XARELTO® in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy.

OVERDOSAGE Overdose of XARELTO® may lead to hemorrhage.

A specific antidote for rivaroxaban is not available.

Rivaroxaban systemic exposure is not further increased at single doses >50 mg due to limited absorption.

Discontinue XARELTO® and initiate appropriate therapy if bleeding complications associated with overdosage occur. The use of activated charcoal to reduce absorption in case of XARELTO® overdose may be considered. Due to the high plasma protein binding, rivaroxaban is not expected to be dialyzable.

ADVERSE REACTIONS IN CLINICAL STUDIES Hemorrhage: The most common adverse reactions with XARELTO® were bleeding complications.

The most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 4.3% for XARELTO® versus 3.1% for warfarin. The incidence of discontinuations for nonbleeding adverse events was similar in both treatment groups. In XARELTO®- versus warfarintreated patients, respectively, major bleeding events were 5.6% versus 5.4%.

Other Clinical Trial Experience: In an investigational study of acute medically ill patients being treated with XARELTO® 10-mg tablets, cases of pulmonary hemorrhage and pulmonary hemorrhage with bronchiectasis were observed.

Please see brief summary of Prescribing Information, including Boxed WARNINGS, on following pages.

Learn more at www.XARELTOhcp.com

Reference: 1. Patel MR, Mahaffey KW, Garg J, et al; and the ROCKET AF Steering Committee, for the ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883-891.

XARELTO® is licensed from Bayer HealthCare AG, 51368 Leverkusen, Germany. © Janssen Pharmaceuticals, Inc. 2011 November 2011 02X11227

Janssen Pharmaceuticals, Inc.

Brief Summary of Prescribing Information for XARELTO® (rivaroxaban) XARELTO® (rivaroxaban) tablets, for oral use See package insert for full Prescribing Information WARNINGS: (A) DISCONTINUING XARELTO IN PATIENTS WITH NONVALVULAR ATRIAL FIBRILLATION INCREASES RISK OF STROKE, (B) SPINAL/EPIDURAL HEMATOMA A. DISCONTINUING XARELTO IN PATIENTS WITH NONVALVULAR ATRIAL FIBRILLATION Discontinuing XARELTO places patients at an increased risk of thrombotic events. An increased rate of stroke was observed following XARELTO discontinuation in clinical trials in atrial fibrillation patients. If anticoagulation with XARELTO must be discontinued for a reason other than pathological bleeding, consider administering another anticoagulant [see Dosage and Administration (2.1) in full Prescribing Information, Warnings and Precautions, and Clinical Studies (14.1) in full Prescribing Information].

B. SPINAL/EPIDURAL HEMATOMA Epidural or spinal hematomas have occurred in patients treated with XARELTO who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include: • use of indwelling epidural catheters • concomitant use of other drugs that affect hemostasis, such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants • a history of traumatic or repeated epidural or spinal punctures • a history of spinal deformity or spinal surgery [see Warnings and Precautions and Adverse Reactions].

Monitor patients frequently for signs and symptoms of neurological impairment.

If neurological compromise is noted, urgent treatment is necessary [see Warnings and Precautions].

Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis [see Warnings and Precautions].

INDICATIONS AND USAGE Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular Atrial Fibrillation: XARELTO (rivaroxaban) is indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

There are limited data on the relative effectiveness of XARELTO and warfarin in reducing the risk of stroke and systemic embolism when warfarin therapy is wellcontrolled [see Clinical Studies (14.1) in full Prescribing Information].

CONTRAINDICATIONS XARELTO is contraindicated in patients with: • active pathological bleeding [see Warnings and Precautions] • severe hypersensitivity reaction to XARELTO [see Warnings and Precautions] WARNINGS AND PRECAUTIONS Increased Risk of Stroke after Discontinuation in Nonvalvular Atrial Fibrillation: Discontinuing XARELTO in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from XARELTO to warfarin in clinical trials in atrial fibrillation patients. If XARELTO must be discontinued for a reason other than pathological bleeding, consider administering another anticoagulant [see Dosage and Administration (2.1) and Clinical Studies (14.1) in full Prescribing Information].

Risk of Bleeding: XARELTO increases the risk of bleeding and can cause serious or fatal bleeding. In deciding whether to prescribe XARELTO to patients at increased risk of bleeding, the risk of thrombotic events should be weighed against the risk of bleeding.

Promptly evaluate any signs or symptoms of blood loss. Discontinue XARELTO in patients with active pathological hemorrhage.

A specific antidote for rivaroxaban is not available. Because of high plasma protein binding, rivaroxaban is not expected to be dialyzable [see Clinical Pharmacology (12.3) in full Prescribing Information]. Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban. There is no experience with antifibrinolytic agents (tranexamic acid, aminocaproic acid) in individuals receiving rivaroxaban. There is neither scientific rationale for benefit nor experience with systemic hemostatics (desmopressin and aprotinin) in individuals receiving rivaroxaban. Use of procoagulant reversal agents such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate (APCC), or recombinant factor VIIa (rFVIIa) may be considered, but has not been evaluated in clinical trials.

Concomitant use of drugs affecting hemostasis increases the risk of bleeding. These include aspirin, P2Y12 platelet inhibitors, other antithrombotic agents, fibrinolytic therapy, and non-steroidal anti-inflammatory drugs (NSAIDs) [see Drug Interactions].

Concomitant use of drugs that are combined P-gp and CYP3A4 inhibitors (e.g. ketoconazole and ritonavir) increases rivaroxaban exposure and may increase bleeding risk [see Drug Interactions].

Spinal/Epidural Anesthesia or Puncture: When neuraxial anesthesia (spinal/epidural anesthesia) or spinal puncture is employed, patients treated with anticoagulant agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis [see Boxed Warning].

An epidural catheter should not be removed earlier than 18 hours after the last administration of XARELTO. The next XARELTO dose is not to be administered earlier than 6 hours after the removal of the catheter. If traumatic puncture occurs, the administration of XARELTO is to be delayed for 24 hours.

Risk of Pregnancy Related Hemorrhage: XARELTO should be used with caution in pregnant women and only if the potential benefit justifies the potential risk to the mother and fetus. XARELTO dosing in pregnancy has not been studied.

The anticoagulant effect of XARELTO cannot be monitored with standard laboratory testing nor readily reversed. Promptly evaluate any signs or symptoms suggesting blood loss (e.g., a drop in hemoglobin and/or hematocrit, hypotension, or fetal distress).

XARELTO® (rivaroxaban) tablets Severe Hypersensitivity Reactions: There were postmarketing cases of anaphylaxis in patients treated with XARELTO to reduce the risk of DVT. Patients who have a history of a severe hypersensitivity reaction to XARELTO should not receive XARELTO [see Adverse Reactions].

ADVERSE REACTIONS Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

During clinical development for the approved indications, 11598 patients were exposed to XARELTO. These included 7111 patients who received XARELTO 15 mg or 20 mg orally once daily for a mean of 19 months (5558 for 12 months and 2512 for 24 months) to reduce the risk of stroke and systemic embolism in nonvalvular atrial fibrillation (ROCKET AF) and 4487 patients who received XARELTO 10 mg orally once daily for prophylaxis of DVT following hip or knee replacement surgery (RECORD 1-3).

Hemorrhage: The most common adverse reactions with XARELTO were bleeding complications [see Warnings and Precautions].

Nonvalvular Atrial Fibrillation: In the ROCKET AF trial, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 4.3% for XARELTO vs. 3.1% for warfarin. The incidence of discontinuations for non-bleeding adverse events was similar in both treatment groups.

Table 1 shows the number of patients experiencing various types of bleeding events in the ROCKET AF study.

Table 1: Bleeding Events in ROCKET AF* Parameter

XARELTO N = 7111 n (%) 395 (5.6) 91 (1.3)

Event Rate (per 100 Pt-yrs) 3.6 0.8

Warfarin N = 7125 n (%) 386 (5.4) 133 (1.9)

Event Rate (per 100 Pt-yrs) 3.5 1.2

Major bleeding† Bleeding into a critical organ‡ Fatal bleeding 27 (0.4) 0.2 55 (0.8) 0.5 Bleeding resulting in 183 (2.6) 1.7 149 (2.1) 1.3 transfusion of ≥ 2 units of whole blood or packed red blood cells Gastrointestinal bleeding 221 (3.1) 2.0 140 (2.0) 1.2 * For all sub-types of major bleeding, single events may be represented in more than one row, and individual patients may have more than one event. † Defined as clinically overt bleeding associated with a decrease in hemoglobin of ≥ 2 g/dL, transfusion of ≥ 2 units of packed red blood cells or whole blood, bleeding at a critical site, or with a fatal outcome. Hemorrhagic strokes are counted as both bleeding and efficacy events. Major bleeding rates excluding strokes are 3.3 per 100 Pt-yrs for XARELTO vs. 2.9 per 100 Pt-yrs for warfarin. ‡ The majority of the events were intracranial, and also included intraspinal, intraocular, pericardial, intraarticular, intramuscular with compartment syndrome, or retroperitoneal.

Postmarketing Experience: The following adverse reactions have been identified during post-approval use of rivaroxaban. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and lymphatic system disorders: agranulocytosis Gastrointestinal disorders: retroperitoneal hemorrhage Hepatobiliary disorders: jaundice, cholestasis, cytolytic hepatitis Immune system disorders: hypersensitivity, anaphylactic reaction, anaphylactic shock Nervous system disorders: cerebral hemorrhage, subdural hematoma, epidural hematoma, hemiparesis Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome DRUG INTERACTIONS Rivaroxaban is a substrate of CYP3A4/5, CYP2J2, and the P-gp and ATP-binding cassette G2 (ABCG2) transporters. Inhibitors and inducers of these CYP450 enzymes or transporters (e.g., P-gp) may result in changes in rivaroxaban exposure.

Drugs that Inhibit Cytochrome P450 3A4 Enzymes and Drug Transport Systems: In drug interaction studies evaluating the concomitant use with drugs that are combined P-gp and CYP3A4 inhibitors, increases in rivaroxaban exposure and pharmacodynamic effects (i.e., factor Xa inhibition and PT prolongation) were observed.

Significant increases in rivaroxaban exposure may increase bleeding risk.

• Ketoconazole (combined P-gp and strong CYP3A4 inhibitor): Steady-state rivaroxaban AUC and Cmax increased by 160% and 70%, respectively. Similar increases in pharmacodynamic effects were also observed.

• Ritonavir (combined P-gp and strong CYP3A4 inhibitor): Single-dose rivaroxaban AUC and Cmax increased by 150% and 60%, respectively. Similar increases in pharmacodynamic effects were also observed.

• Clarithromycin (combined P-gp and strong CYP3A4 inhibitor): Single-dose rivaroxaban AUC and Cmax increased by 50% and 40%, respectively. The smaller increases in exposure observed for clarithromycin compared to ketoconazole or ritonavir may be due to the relative difference in P-gp inhibition.

• Erythromycin (combined P-gp and moderate CYP3A4 inhibitor): Both the single-dose rivaroxaban AUC and Cmax increased by 30%.

• Fluconazole (moderate CYP3A4 inhibitor): Single-dose rivaroxaban AUC and Cmax increased by 40% and 30%, respectively.

Avoid concomitant administration of XARELTO with combined P-gp and strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, lopinavir/ritonavir, ritonavir, indinavir/ ritonavir, and conivaptan), which cause significant increases in rivaroxaban exposure that may increase bleeding risk.

XARELTO® (rivaroxaban) tablets

XARELTO® (rivaroxaban) tablets

Drugs that Induce Cytochrome P450 3A4 Enzymes and Drug Transport Systems: In a drug interaction study, co-administration of XARELTO (20 mg single dose with food) with a drug that is a combined P-gp and strong CYP3A4 inducer (rifampicin titrated up to 600 mg once daily) led to an approximate decrease of 50% and 22% in AUC and Cmax, respectively. Similar decreases in pharmacodynamic effects were also observed. These decreases in exposure to rivaroxaban may decrease efficacy.

Avoid concomitant use of XARELTO with drugs that are combined P-gp and strong CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampin, St. John’s wort).

Anticoagulants: In a drug interaction study, single doses of enoxaparin (40 mg subcutaneous) and XARELTO (10 mg) given concomitantly resulted in an additive effect on anti-factor Xa activity. Enoxaparin did not affect the pharmacokinetics of rivaroxaban. In another study, single doses of warfarin (15 mg) and XARELTO (5 mg) resulted in an additive effect on factor Xa inhibition and PT. Warfarin did not affect the pharmacokinetics of rivaroxaban.

NSAIDs/Aspirin: In ROCKET AF, concomitant aspirin use (almost exclusively at a dose of 100 mg or less) during the double-blind phase was identified as an independent risk factor for major bleeding. NSAIDs are known to increase bleeding, and bleeding risk may be increased when NSAIDs are used concomitantly with XARELTO. In a singledose drug interaction study there were no pharmacokinetic or pharmacodynamic interactions observed after concomitant administration of naproxen or aspirin (acetylsalicylic acid) with XARELTO. Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with aspirin, other platelet aggregation inhibitors, or NSAIDs [see Warnings and Precautions].

Clopidogrel: In two drug interaction studies where clopidogrel (300 mg loading dose followed by 75 mg daily maintenance dose) and XARELTO (15 mg single dose) were co-administered in healthy subjects, an increase in bleeding time to 45 minutes was observed in approximately 45% and 30% of subjects in these studies, respectively. The change in bleeding time was approximately twice the maximum increase seen with either drug alone. There was no change in the pharmacokinetics of either drug.

Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with clopidogrel [see Warnings and Precautions].

Drug-Disease Interactions with Drugs that Inhibit Cytochrome P450 3A4 Enzymes and Drug Transport Systems: Based on simulated pharmacokinetic data, patients with renal impairment receiving full dose XARELTO in combination with drugs classified as combined P-gp and weak or moderate CYP3A4 inhibitors (e.g., amiodarone, diltiazem, verapamil, quinidine, ranolazine, dronedarone, felodipine, erythromycin, and azithromycin) may have significant increases in exposure compared with patients with normal renal function and no inhibitor use, since both pathways of rivaroxaban elimination are affected.

While increases in rivaroxaban exposure can be expected under such conditions, results from an analysis in the ROCKET AF trial, which allowed concomitant use with combined P-gp and weak or moderate CYP3A4 inhibitors (e.g., amiodarone, diltiazem, verapamil, chloramphenicol, cimetidine, and erythromycin), did not show an increase in bleeding in patients with CrCl 30 to <50 mL/min [Hazard Ratio (95% CI): 1.05 (0.77, 1.42)]. XARELTO should be used in patients with CrCL 15 to 50 mL/min who are receiving concomitant combined P-gp and weak or moderate CYP3A4 inhibitors only if the potential benefit justifies the potential risk [see Use in Specific Populations].

USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category C: There are no adequate or well-controlled studies of XARELTO in pregnant women, and dosing for pregnant women has not been established. Use XARELTO with caution in pregnant patients because of the potential for pregnancy related hemorrhage and/or emergent delivery with an anticoagulant that is not readily reversible. The anticoagulant effect of XARELTO cannot be reliably monitored with standard laboratory testing. Animal reproduction studies showed no increased risk of structural malformations, but increased post-implantation pregnancy loss occurred in rabbits. XARELTO should be used during pregnancy only if the potential benefit justifies the potential risk to mother and fetus [see Warnings and Precautions].

Rivaroxaban crosses the placenta in animals. Animal reproduction studies have shown pronounced maternal hemorrhagic complications in rats and an increased incidence of post-implantation pregnancy loss in rabbits. Rivaroxaban increased fetal toxicity (increased resorptions, decreased number of live fetuses, and decreased fetal body weight) when pregnant rabbits were given oral doses of ≥10 mg/kg rivaroxaban during the period of organogenesis. This dose corresponds to about 4 times the human exposure of unbound drug, based on AUC comparisons at the highest recommended human dose of 20 mg/day. Fetal body weights decreased when pregnant rats were given oral doses of 120 mg/kg. This dose corresponds to about 14 times the human exposure of unbound drug.

Labor and Delivery: Safety and effectiveness of XARELTO during labor and delivery have not been studied in clinical trials. However, in animal studies maternal bleeding and maternal and fetal death occurred at the rivaroxaban dose of 40 mg/kg (about 6 times maximum human exposure of the unbound drug at the human dose of 20 mg/day).

Nursing Mothers: It is not known if rivaroxaban is excreted in human milk.

Rivaroxaban and/or its metabolites were excreted into the milk of rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from rivaroxaban, a decision should be made whether to discontinue nursing or discontinue XARELTO, taking into account the importance of the drug to the mother.

Pediatric Use: Safety and effectiveness in pediatric patients have not been established.

Geriatric Use: Of the total number of patients in the RECORD 1-3 clinical studies evaluating XARELTO, about 54% were 65 years and over, while about 15% were >75 years. In ROCKET AF, approximately 77% were 65 years and over and about 38% were >75 years. In clinical trials the efficacy of XARELTO in the elderly (65 years or older) was similar to that seen in patients younger than 65 years. Both thrombotic and bleeding event rates were higher in these older patients, but the risk-benefit profile was favorable in all age groups [see Clinical Pharmacology (12.3) and Clinical Studies (14) in full Prescribing Information].

Females of Reproductive Potential: Females of reproductive potential requiring anticoagulation should discuss pregnancy planning with their physician.

Renal Impairment: The safety and pharmacokinetics of single-dose XARELTO (10 mg) were evaluated in a study in healthy subjects [CrCl ≥80 mL/min (n=8)] and in subjects with varying degrees of renal impairment (see Table 2). Compared to healthy subjects with normal creatinine clearance, rivaroxaban exposure increased in subjects with renal impairment. Increases in pharmacodynamic effects were also observed.

Table 2: Percent Increase of Rivaroxaban PK and PD Parameters from Normal in Subjects with Renal Insufficiency from a Dedicated Renal Impairment Study Renal Impairment Class [CrCl (mL/min)] Parameter Mild Moderate Severe [50 to 79] [30 to 49] [15 to 29] N=8 N=8 N=8 Exposure AUC 44 52 64 28 12 26 (% increase relative to normal) Cmax FXa Inhibition AUC 50 86 100 9 10 12 (% increase relative to normal) Emax PT Prolongation AUC 33 116 144 4 17 20 (% increase relative to normal) Emax PT = Prothrombin time; FXa = Coagulation factor Xa; AUC = Area under the concentration or effect curve; Cmax = maximum concentration; Emax = maximum effect; and CrCl = creatinine clearance Patients with renal impairment taking P-gp and weak to moderate CYP3A4 inhibitors may have significant increases in exposure which may increase bleeding risk [see Drug Interactions].

Nonvalvular Atrial Fibrillation: In the ROCKET AF trial, patients with CrCl 30 to 50 mL/min were administered XARELTO 15 mg once daily resulting in serum concentrations of rivaroxaban and clinical outcomes similar to those in patients with better renal function administered XARELTO 20 mg once daily. Patients with CrCl 15 to 30 mL/min were not studied, but administration of XARELTO 15 mg once daily is also expected to result in serum concentrations of rivaroxaban similar to those in patients with normal renal function [see Dosage and Administration (2.1) in full Prescribing Information].

Hepatic Impairment: The safety and pharmacokinetics of single-dose XARELTO (10 mg) were evaluated in a study in healthy subjects (n=16) and subjects with varying degrees of hepatic impairment (see Table 3). No patients with severe hepatic impairment (Child-Pugh C) were studied. Compared to healthy subjects with normal liver function, significant increases in rivaroxaban exposure were observed in subjects with moderate hepatic impairment (Child-Pugh B). Increases in pharmacodynamic effects were also observed.

Table 3: Percent Increase of Rivaroxaban PK and PD Parameters from Normal in Subjects with Hepatic Insufficiency from a Dedicated Hepatic Impairment Study Hepatic Impairment Class (Child-Pugh Class) Parameter Mild Moderate (Child-Pugh A) (Child-Pugh B) N=8 N=8 Exposure AUC 15 127 0 27 (% increase relative to normal) Cmax FXa Inhibition AUC 8 159 0 24 (% increase relative to normal) Emax PT Prolongation AUC 6 114 2 41 (% increase relative to normal) Emax PT = Prothrombin time; FXa = Coagulation factor Xa; AUC = Area under the concentration or effect curve; Cmax = maximum concentration; Emax = maximum effect Avoid the use of XARELTO in patients with moderate (Child-Pugh B) and severe (ChildPugh C) hepatic impairment or with any hepatic disease associated with coagulopathy [see Dosage and Administration (2.3) in full Prescribing Information and Warnings and Precautions].

OVERDOSAGE Overdose of XARELTO may lead to hemorrhage. A specific antidote for rivaroxaban is not available. Rivaroxaban systemic exposure is not further increased at single doses >50 mg due to limited absorption. Discontinue XARELTO and initiate appropriate therapy if bleeding complications associated with overdosage occur. The use of activated charcoal to reduce absorption in case of XARELTO overdose may be considered. Due to the high plasma protein binding, rivaroxaban is not expected to be dialyzable [see Warnings and Precautions and Clinical Pharmacology (12.3) in full Prescribing Information].

Active Ingredient Made in Germany Finished Product Manufactured by: Janssen Ortho, LLC Gurabo, PR 00778

Manufactured for: Janssen Pharmaceuticals, Inc. Titusville, NJ 08560

© Janssen Pharmaceuticals, Inc. 2011 10185201 02X11309BBA

Licensed from: Bayer HealthCare AG 51368 Leverkusen, Germany

CME CE

Dermatology Clinic ■ LEARNING OBJECTIVES: To identify and diagnose dermatologic conditions and review up-to-date treatment.

■ COMPLETE THE POSTTEST: Page 70

■ ADDITIONAL CME/CE: Pages 23, 65

Turn to page 22 for additional information on this month’s CME/CE courses.

CASE #1

Macules spread from abdomen to extremities KERRI ROBBINS, MD

An otherwise healthy Hispanic woman, age 43 years, presented to the dermatology clinic for evaluation of a rash. The rash had begun approximately 18 months earlier and started as dark spots on her abdomen that had since spread to involve her proximal extremities.

No pruritus or pain was reported, and no new medications were used prior to the onset of the rash. No treatment had been attempted. On clinical examination, numerous ash-gray to blue macules coalescing into patches were seen in a symmetric distribution on the trunk and proximal extremities.

What is your diagnosis? Turn to page 60

CASE #2

Pink nodule on the crown of the head ESTHER STERN, NP-C

A 78-year-old woman with Alzheimer disease was brought in for evaluation of a scalp lesion first noticed by her granddaughter one month earlier. Because of her dementia, the patient was unable to provide a reliable history. Her granddaughter reported no patient or family history of previous skin cancer or other malignancy.

Physical examination revealed a 10-mm × 5-mm pink, somewhat pearly, and firm nodule on the vertex of the scalp. Examination of the head and neck was otherwise unremarkable, and no appreciable adenopathy was detected.

What is your diagnosis? Turn to page 61 www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MAY 2012 59

CME CE

CASE #1

Dermatology Clinic

Erythema dyschromicum perstans

Er ythema dyschromicum perstans (EDP) is a disorder that most commonly affects Latin Americans and Asians.

However, there have been cases reported in Caucasians as well, particularly individuals with skin types III and IV.1 Although some researchers claim that EDP affects women more than men, there are no key findings to support this.

The age of onset has a wide range, most commonly affecting those between the first and third decade of life. There have been cases reported in those who were as young as age 1 year and as old as age 80 years.

EDP has no known pathogenesis. It has been suggested that the condition is a cell-mediated immune reaction against an ingestant, which leads to pigmentary incontinence. In 1973, Pinkus claimed EDP was caused by the effects of environmental pollution in genetically susceptible individuals.1,2 The retrospective examination of various patients has led to the development of a variety of possible predisposing factors, none of which is consistent, however. These factors include orally administered radiographic media (barium sulfate), ammonium nitrates, fertilizer, pesticides, fungicides, and such drugs as penicillin and benzodiazepines.2,3 Other possible etiologies include whipworm infections (intestinal parasitosis caused by nematodes) and HIV. Even chlorothalonil from bananas has been raised as a possible cause of EDP. Genetic research has shown an HLA-DR4 allele association with EDP in some Hispanic patients.4 The major histocompatibility complex region is believed to house the genes responsible for the disease. Examination of immunologic chemistry demonstrates expression of cell adhesion molecules as well as lymphocyte activation molecules. No specific or consistent microbe, drug, or agent has been identified as the cause, and more research is needed in this area. Numerous laboratory experiments in persons with EDP have shown negative results for bacterial, viral, and mycologic studies. Evaluations of such tests as a complete blood count, comprehensive metabolic panel, and urinalysis have not shown any abnormalities in patients with EDP. EDP is a slow, progressive, acquired, and chronic hyperpigmentation. The ash-gray to blue macules start small but think big; they progress slowly and eventually grow to cover large areas of the body. The macules and patches may

be oval, with their long axes following skin cleavage lines (circular or irregularly shaped). Macules/patches range in diameter from 0.5 cm to 2.5 cm.1 They are uncommonly surrounded by an erythematous peripheral margin that can measure 1 mm to 2 mm in diameter.1 The macules can cover a wide area of the body and tend to occur in a symmetrical pattern on the trunk, face, neck, and proximal upper extremities. The lesions do not affect mucous membranes and rarely progress to the palms, soles, or scalp. EDP is generally asymptomatic, but some patients have reported pruritus. For the most part, the disease does not regress in

The ash-gray to blue macules start small and progress slowly and eventually grow to cover large areas of the body. adults; however, there have been a few cases in children in which spontaneous regression has occurred.5,6 Histologic findings will vary depending on the age of the lesion. In the early stage, the erythematous border (active region) will show vacuolar alteration of the basal layer.

Necrotic keratinocytes or colloid bodies may be occasionally seen.7 Melanophages will be mingled with a perivascular and/or lichenoid infi ltrate of lymphocytes and histiocytes within the dermis.8 Later in the development of EDP, the ash-gray lesions (inactive region) may have a considerable amount of epidermal change; these include atrophy and effacement of the normal pattern of rete ridges.8 There is also a considerable amount of pigment incontinence.

Since its discovery, some researchers and authors have regarded EDP as a variant of lichen planus due to the similarity of their clinical and histologic features. Direct immunofluorescence studies of the active border of EDP have shown immunoglobulin (Ig)M, IgG, and fibrinogen, just as is seen with lichen planus. However, EDP will often only demonstrate fibrinogen at the dermal-epidermal junction.1 Additionally, immunofluorescence studies have shown the dermal infiltrate to be composed of CD4+ and CD8+ T cells, also commonly seen in lichen planus. Making the clinical distinction between the two conditions may be difficult.

Lichen planus is usually distinguished clinically by flat-topped papules and plaques, which are features not seen in EDP. Fixed-drug eruptions (FDEs) must also be in the differential diagnosis. The infiltrate and pigmentary incontinence seen in FDEs may appear very similar to EDP. However, the lesions

60 THE CLINICAL ADVISOR â&#x20AC;˘ MAY 2012 â&#x20AC;˘ www.ClinicalAdvisor.com

CME CE

Dermatology Clinic

seen in FDEs are often more circular and brown in color.

Pityriasis rosea, small plaque parapsoriasis, post-inflammatory hyperpigmentation, melasma, erythema multiforme, and other drug reactions must also be considered.

EDP is chronic, and there are no effective treatments for the disease. Topical corticosteroids, hydroquinone, and sun protection have been ineffective in treating EDP. Retinoids, vitamin C, vitamin A, chemical peels, UV light therapy, antimarials, and antibiotics have all failed to produce any significant results.1 In a small series, treatment with dapsone and clofazimine (Lamprene) was reported as effective.1 EDP is benign and will not cause death. Lesions have been known to spontaneously resolve in prepubertal children but often chronically persist in adults.5,6 Most patients will be concerned about cosmetic issues related to the disease and may suffer from anxiety and depression. The unpleasant sight of the blue-grayish lesions can cause significant damage to the patient’s self-esteem. As always, it is important for clinicians to pay close attention to the patient’s emotions and psychological distress.

The patient in this case was counseled on the chronic nature of the disease and the poor treatment regimens available. She was given reassurance and strongly advised to use sun protection. ■ Dr. Robbins is a resident in the Department of Dermatology at Baylor College of Medicine in Houston.

References 1. Bolognia JL, Jorizzo JL, Rapini RP eds. Dermatology. 2nd ed. St. Louis, Mo.: Elsevier Mosby; 2008:178-179, 940-942.

2. Pinkus H. Lichenoid tissue reactions. A speculative review of the clinical spectrum of epidermal basal cell damage with special reference to erythema dyschromicum perstans. Arch Dermatol. 1973;107:840-846.

3. Schwartz RA. Erythema dyschromicum perstans: the continuing enigma of Cinderella or ashy dermatosis. Int J Dermatol. 2004;43:230-232.

4. Correa MC, Memije EV, Vargas-Alarcón G, et al. HLA-DR association with the genetic susceptibility to develop ashy dermatosis in Mexican Mestizo patients. J Am Acad Dermatol. 2007;56:617-620.

5. Lee SJ, Chung KY. Erythema dyschromicum perstans in early childhood.

J Dermatol. 1999; 26:119-121.

6. Paller AS, Mancini AJ. Hurwitz Clinical Pediatric Dermatology. 3rd ed.

Philadelphia, Pa.: Elsevier Saunders; 2006:293-294.

7. RP Rapini. Practical Dermatopathology. Philadelphia, Pa.: Elsevier Mosby; 2005:70.

8. Elder DE, Elenitsas R, Johnson BL, et al, eds. Lever’s Histopathology of the Skin. 10th ed. Philadelphia, Pa.: Lippincott Williams & Wilkins; 2009:172-173.

CASE #2

Cutaneous angiosarcoma

Histopathology findings were consistent with a diagnosis of cutaneous angiosarcoma (AS).

ASs are a group of rare malignant sarcomas originating from neoplastic transformation of the vascular endothelial cells.

Most ASs are known to be very aggressive, with a high rate of metastases and mortality. Both the intrinsic biologic properties of the tumor and the high rate of misdiagnosis contribute to the poor prognosis.

Although AS may arise in almost any organ, the skin and soft tissue are most commonly found to be the primary tumor site. Cutaneous AS, which originates in the skin, accounts for approximately 60% off all ASs.1 The five-year survival rate for cutaneous AS is dismal and estimated to be approximately 30%.2 Prognosis is poorer in those individuals with tumor external diameter greater than 5 cm, depth of invasion greater than 3 mm, positive surgical margins, metastases, and tumor recurrence.3 Risk factors for AS include a history of radiation therapy; lymphedema; exposure to such toxins as arsenic, Thorotrast (a radioactive contrast dye used in radiology from about 1930 to the mid-1950s), and polyvinyl chloride (used in plastics); and presence of such foreign bodies as bone wax, dialysis shunts made of Dacron, metal bodies, surgical sponges, and plastic graft material. In addition, AS occurs more frequently in individuals with AIDS. Cutaneous AS is divided into four variants: (1) AS of the head and neck; (2) Stewart-Treves variant, occurring in the context of lymphedema; (3) radiation-induced AS; and (4) epithelioid AS. AS of the head and neck, also known as Wilson-Jones AS, is the most common form and occurs almost exclusively in the elderly. The male-to-female ratio is approximately 2:1.

The tumor initially appears as an ill-defined bluish macule that is frequently mistaken for a bruise or cellulitis. With time, the tumor grows and evolves into an indurated bluish nodule or plaque that is usually asymmetric, nodular, or ulcerated. Spontaneous localized bleeding, satellite nodules, intratumoral hemorrhage, and a peripheral erythematous ring are other distinguishing features of AS of the head and neck. Systemic bleeding or altered coagulation are ominous signs and usually indicative of metastases.

Continues on page 62

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MAY 2012 61

CME CE

Dermatology Clinic

The Stewart-Treves variant, or lymphedema-associated AS, develops in an area of the skin affected with chronic lymphedema. This variant is most frequently seen in the upper arm of a post-mastectomy patient, with an estimated 0.07% to 0.45% prevalence rate post-mastectomy.1 Stewart-Treves is seen less commonly in patients with a history of lymph node dissection or chronic idiopathic lymphedema. Although there is no known cause for the correlation between AS and lymphedema, several theories exist. Some believe that the decreased clearance of the local lymph node causes the surrounding tissue to be chronically exposed to carcinogens.

Others propose that the lymph node removal triggers angiogenesis, subsequently allowing for the growth of malignant cells. Lymphedema-associated AS occurs an average of 10 to 12 years postsurgery. This subtype usually appears as a violaceous ulcerating plaque or nodule superimposed on a background of brawny, nonpitting edema.

The third subtype, radiation-induced AS, occurs anywhere from four to 40 years postradiation exposure. Quicker disease onset is seen in those patients who were treated with radiation for a malignant condition rather than for a benign condition. These tumors present initially with ecchymosis or thickening of the skin within a previously radiated area.

The fi nal subtype includes a rare and more recently discovered aggressive variant called epithelioid AS. Because epithelioid AS often mimics common vascular and nonvascular neoplasms histologically, both a high clinical index of suspicion and an expert thorough histopathologic examination is needed.4 Biopsy of the tumor allows for diagnosis. Care should be taken to provide proper hemostasis after the biopsy to avoid blood extravasation, which would allow for dissemination of the tumor cells. Diagnosis is based on the microscopic features of the biopsy specimen and ultrastructural and histochemical markers. On microscopy, AS will present with irregularly shaped vascular spaces lined with atypical endothelial tumor cells. Unlike benign hemangiomas, AS vascular channels disrupt normal tissue planes and form a network of sinusoids.

Tumors are often characterized as well-differentiated (low-grade), moderately differentiated, or poorly differentiated (high-grade). Well-differentiated tumors are more easily diagnosed, while the latter may require special staining techniques to aid in identification.

MRI and/or CT imaging studies should be performed as part of the initial workup, as up to 50% of patients will have evidence of metastasis at the time of diagnosis.

Individuals diagnosed with AS should be referred to a multidisciplinary cancer center. For limited disease, complete surgical excision of the macroscopic tumor followed by moderate-dose and wide-field radiation offers the best opportunity for cure.5 Surgical treatment is contraindicated in patients with tumors that extend into vital organs or those that are of very large size. Systemic therapies are limited, but chemotherapy with doxorubicin (Adriamycin, Rubex) followed by radiotherapy is a reasonable approach.6 Newer

On microscopy, angiosarcoma will present with irregularly shaped vascular spaces lined with atypical endothelial tumor cells. therapeutic options may include antiangiogenic, immunotherapy, and multimodality treatments. Unfortunately, treatment for extensive disease is mostly palliative.

All patients with angiosarcoma should be closely monitored for life. Recurrences may occur years later or as early as two years post-cure.

The patient in this case was referred to a hematologist/ oncologist for treatment. Presurgical workup revealed no sign of metastases, and primary surgical removal was planned.

Unfortunately, the patient was lost to follow-up. ■ Ms. Stern is a family nurse practitioner at Advanced Dermatology & Skin Surgery, P.C., in Lakewood, N.J. References 1. Liddy Shriver Sarcoma Initiative. Angiosarcoma. Available at sarcomahelp .org/learning_center/angiosarcoma.html.

2. Fury MG, Antonescu CR, Van Zee KJ, et al. A 14-year retrospective review of angiosarcoma: clinical characteristics, prognostic factors, and treatment outcomes with surgery and chemotherapy. Cancer J. 2005;11:241-247.

3. Morgan MB, Swann M, Somach S, et al. Cutaneous angiosarcoma: a case series with prognostic correlation. J Am Acad Dermatol. 2004;50:867-874.

4. Mobini N. Cutaneous epithelioid angiosarcoma: a neoplasm with potential pitfalls in diagnosis. J Cutan Pathol. 2009;36:362-369.

5. Morrison WH, Byers RM, Garden AS, et al. Cutaneous angiosarcoma of the head and neck. A therapeutic dilemma. Cancer. 1995;76:319-327.

6. Wollina U, Füller J, Graefe T, et al. Angiosarcoma of the scalp: treatment with liposomal doxorubicin and radiotherapy. J Cancer Res Clin Oncol.

2001;127:396-369.

All electronic documents accessed April 15, 2012.

62 THE CLINICAL ADVISOR • MAY 2012 • www.ClinicalAdvisor.com

ALTERNATIVE MEDS UPDATE What you should know about the herbs and supplements patients use

By Sherril Sego, FNP-C, DNP. Ms. Sego is a staff clinician at the VA Hospital in Kansas City, Mo., where she practices adult medicine and women’s health. She also teaches at the nursing schools of the University of Missouri and the University of Kansas.

Tart cherry

© ISTOCKPHOTO.COM / SANDY JONES

Tart cherries are a source of antioxidants that are fast emerging as a superfruit. A growing body of evidence has linked the tart cherry to substantial anti-inflammatory benefits, including reduced arthritic and gout pain, and several cardiac benefits.

Prunus cerasus—the sour cherry—is the smallest of the stone fruits.1 It’s sweeter cousins—the Bing, Rainier, and Lambert cherries—are usually eaten raw and are slightly larger than sour cherries. Tart cherries are typically reserved for making pies and preserves. So, the next time you feel like indulging in a piece of cherry pie, remember that you can—sort of—justify the indulgence.

Background Tart cherries contain several potent antioxidants—among them anthocyanins—which give the cherries their rich, distinctive color.2 In addition, tart cherries have been found to contain a unique set of antioxidative compounds, called superoxide disumutase, that are even more potent than the anthocyanins.2

Science Multiple studies have explored using tart cherry juice to offset inflammation. One study examined the effect of cherry juice consumption on rapid-onset oxidative stress. Researchers enrolled 20 recreational marathon runners into a placebocontrolled trial and gave the active treatment group cherry juice prior to and just after the race.3 Isometric strength, muscle enzymes, and inflammatory markers were measured in each participant after the marathon. Data showed that the cherry-juice cohort recovered isometric strength faster

and showed lower levels of such inflammatory markers as C-reactive protein (CRP) and interleukin-6 than did the placebo group.3 Tart cherry juice was also tested in connection with its ability to relieve oxidative stress and muscle damage in the elderly.

One study examined 12 healthy volunteers aged 61-75 years.4,5 Each group was given one cup (240 ml) of either cherry juice or flavored water twice daily for two weeks.4,5 Subsequent measurements of oxidized amino acids in urinary output were less in the active treatment group when compared to the placebo, indicating lower levels of cellular damage.4,5 In a small trial, 10 obese volunteers (BMI 27.0-36.0) were studied for potential cardiovascular benefits connected to tart cherry ingestion. Respective cohorts received eight ounces of tart cherry juice or flavored water daily for four weeks.6 At the end of the trial, glucose, high-sensitivity CRP (hsCRP), total cholesterol, triglycerides, LDL, VLDL, and HDL cholesterol were measured and compared to baseline. Of the measurements, triglycerides and VLDL were significantly

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MAY 2012 63

ALTERNATIVE MEDS UPDATE reduced in the cherry-juice group, suggesting a reduction in cardiovascular risk.6 Tart cherry juice has also been studied in connection with its effect on arthritic and rheumatologic conditions. In a recently published study, 59 arthritis patients were given 240 ml of cherry juice twice daily for six weeks, and placebo patients were given flavored water.7 At the end of the study, the juice drinkers had significantly decreased hs-CRP levels and pain scores on the Western Ontario and McMaster Universities Arthritis Index (WOMAC), and some subjects noted unsolicited subjective pain relief.7 Study participants were administered the standardized WOMAC questionnaire to accurately determine symptom scores.7 An added benefit of tart cherry juice is that it contains melatonin. Known as the hormone influencing human sleep cycles, melatonin is a potential antioxidant.8 Given this source of exogenous melatonin, studies show improvements in sleep latency, sleep time, and overall sleep efficacy.8 Two randomized, placebo-controlled trials studied 35 healthy adults with complaints of sleepcycle disturbances.8,9 Active-treatment group participants were given daily supplementation of two 8-oz servings of tart cherry juice formulation per day.8,9 Both trials verified improved scores on all study variables, including total sleep time, sleep-cycle efficacy, and sleep latency, as wll as urinary excretion of melatonin.8,9

powder-fi lled capsules. The dose considered in most studies is the equivalent of 8 oz of pure cherry juice each day. Many of the extracts and powders on the market are concentrated, reducing the fluid volume to as little as 1 oz.

Cost varies with the type of product, ranging from $15 to $50 for a one-month supply.

Summary Tart cherries are a safe product for individuals seeking a healthy, broad-spectrum antioxidant to add to their daily arsenal. ■ In clinical trials, tart cherry juice was found to aid sleep efficiency.

References 1. Alternative medicine supplements page. About.

A growing body of evidence has linked the tart cherry to several antiinflammatory benefits.

com website. Available at altmedicine.about.com/od/ completeazindex/a/tart_cherry.htm.

2. USDA nutrient data laboratory page. United States Department of Agriculture website. Available at www.ars.usda.gov/nutrientdata.

3. Howatson G, McHugh MP, Hill JA, et al. Influence of tart cherry juice on indices of recovery following marathon running. Scan J Med Sci Sports. 2010;20:843-852.

4. Connolly DA, McHugh MP, Padilla-Zakour OI, et al.

Efficacy of a tart cherry juice blend in preventing the symptoms of muscle damage. Br J Sports Med. 2006;40:679-683.

5. Traustadottir T, Davies SS, Stock AA, et al. Tart cherry juice decreases oxidative stress in healthy older men and women. J Nutr. 2009;139:1896-1900. Available at jn.nutrition.org/content/139/10/1896.long.

6. Martin K, Bopp J, Neupane S, Vega-Lopez S. Tart cherry juice reduces plasma triglycerides and CVD risk in overweight

Safety, interactions

and obese subjects. J Am Soc Exp Biol. 2010;37:722-740.

7. Schumacher R. Double blind cross-over study of the efficacy of a tart cherry juice blend in treatment of osteoarthritis (OA) of the knee. Poster abstract: 2011 American College of Rheumatology Scientific Meeting, Chicago.

8. Howatson G, Bell, PG, Tallent J, et al. Effect of tart cherry juice (Prunus cerasus) on melatonin levels and enhanced sleep quality. Eur J Nutr. 2011;13:579-83.

9. Pigeon WR, Carr M, Gorman C, Perlis ML. Effects of a tart cherry juice beverage on the sleep of older adults with insomnia: A pilot study. J Med Food. 2010;13:579-

Dosage and cost

583. Available at www.ncbi.nlm.nih.gov/pmc/articles/ PMC3133468/.

Tart cherries are available in almost any form— as fresh fruit, dried fruit, juice extracts, and 64 THE CLINICAL ADVISOR • MAY 2012 • www.ClinicalAdvisor.com

All electronic documents accessed on April 15, 2012

© ISTOCKPHOTO.COM / NICOLAS HANSEN

Tart cherries contain significant amounts of sorbitol, a sugar alcohol that has been known to trigger symptoms in people with irritable bowel syndrome. Caution should also be used when administering tart-cherry therapy in patients who are taking warfarin, since the high-level of antioxidants may activate warfarin’s antithrombotic action.

CME CE

Dermatologic Look-Alikes ■ LEARNING OBJECTIVE: To distinguish and properly treat dermatologic conditions with similar presentations.

■ COMPLETE THE POSTTEST: Page 70

■ ADDITIONAL CME/CE: Pages 23, 59

Turn to page 22 for additional information on this month’s CME/CE courses.

Bimalar facial rashes JOE R. MONROE, MPAS, PA

CASE #1

CASE #2

A nurse, age 54 years, arrived for evaluation of what she and her fellow hospital workers presumed to be lupus.

The rash had been present for approximately one month.

Such systemic symptoms as joint pain, fever, and malaise were not reported. The rash burned and itched and had persisted despite the application of a number of OTC creams and ointments. An antinuclear antibody (ANA) test ordered by the patient’s primary-care provider was nonreactive. A complete blood count and comprehensive metabolic profi le showed no abnormal results.

A 26-year-old woman first noticed a facial rash early in the summer but had to wait several weeks before she could be seen in the dermatology clinic. Feeling the need to try something in the meantime, she used OTC moisturizers and 1% hydrocortisone cream to obtain relief from mild itching and burning. Neither of the OTC treatments was helpful, and the rash grew more erythematous. The woman’s symptoms were particularly exacerbated after a day spent in the sun working as a landscaper.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MAY 2012 65

CME CE

CASE #1

Dermatologic Look-Alikes

Seborrheic dermatitis

Every medical student hears about the butterf ly rash of lupus. However, the classic bimalar rash of lupus is not at all common, even in conf irmed lupus cases.

Additionally, as with virtually all medical diagnoses, there is a differential for florid facial rashes that includes a number of far more common conditions, including contact vs. irritant dermatitis, psoriasis, and seborrheic dermatitis.1 This patient’s rash was reddish-orange and florid, affecting sharply demarcated convex areas of the cheeks, chin, and forehead, where the lesions took on more of an annular morphology. The nasal bridge was spared. Little if any edema was appreciated, and there was no increase in surface warmth in the areas. A KOH examination of scrapings from the surfaces of the lesions showed no fungal elements or signs of Demodex, a mite that is part of normal flora inhabiting follicles and sebaceous glands, especially in periocular areas, and occasionally implicated in rosacealike facial eruptions.2 Approximately 95% of systemic lupus cases are ANApositive. The negative ANA in this case served only to rule out systemic lupus erythematosus, since seronegative cutaneous lupus can still present in a wide variety of ways, including facial involvement. A 3-mm biopsy was performed and showed none of the features consistent with lupus (i.e., vacuolar interface dermatitis, a universal finding in active lupus lesions). Such other findings consistent with lupus as parakeratosis and mild hyperkeratosis were also missing in this case.1 Instead, spongiotic dermatitis with mild follicular accentuation was seen in this patient. While not diagnostic, these changes made lupus less likely, as did the lack of such other findings as atrophy, dilated follicles, or alopecia.2 Clinicians were also able to rule out sarcoidosis, polymorphous light eruption, lichen planus, tertiary syphilis,

MORE DERMATOLOGY ON THE WEB Test your diagnostic skills. Our FREE archive of Dermatology Clinic and Dermatologic Look-Alikes is now available online at www.ClinicalAdvisor.com/Derm.

and lymphocytic infi ltration of Jessner, all of which would have shown fi ndings suggestive—if not diagnostic—of those entities.

Unfortunately, a diagnosis of spongiotic dermatitis, however useful, only gains the clinician admission to a rather large ballpark and not to a specific seat. Commonly seen in irritant and contact dermatoses, spongiosis simply implies intercellular edema of the epidermis triggered by inflammation.3 “Clinical correlation” comes into play at this point, which involves a more in-depth discussion with the patient to determine exactly when and how this condition started and whether there is any history of skin problems or other significant medical problems or family history of such skin diseases as psoriasis. It is also helpful to ask which products had been used to treat the rash.

The woman described in this case was desperate to obtain relief and had used a number of products on her face over

It is very common for self-prescribed “treatment” to cause far more problems than the original condition. the first few weeks of her rash. She was advised to stop all topical products except those prescribed by a clinician. It is extremely common for a patient’s self-prescribed “treatment” to cause far more problems than the original condition he or she set out to remedy. Neither stopping OTC treatment nor ceasing b.i.d. application of topical desonide (DesOwen, Tridesilon) lotion was successful in controlling the woman’s rash.

There was no family history of skin disease, but the patient did recall having a milder version of her current outbreak on a number of occasions over the years. In the past, these eruptions had always involved the same areas of her face as well as the scalp and bilateral postauricular skin. These episodes always were preceded by periods of exceptional emotional stress. The patient did confirm that similar conditions had preceded this most recent eruption, and examination confirmed the involvement of the skin behind and in both ears with a shiny and scaly rash similar to the one on her face.

A diagnosis of seborrheic dermatitis—possibly worsened by irritation brought on by use of OTC products—was eventually made. Seborrheic dermatitis is an extremely

66 THE CLINICAL ADVISOR • MAY 2012 • www.ClinicalAdvisor.com

CME CE

Dermatologic Look-Alikes

common papulosquamous condition that affects up to 20% of the population. Its most common form is that of dandruff, but seborrheic dermatitis also manifests as a minimally scaly and pinkish-red rash on nasolabial folds, beard area, glabella, eyebrows, and in and behind the ears. Thought to represent an abnormal response to the commensal yeast Malassezia furfur, seborrheic dermatitis can affect a wide array of other anatomic areas as well, including the trunk, chest, axillae, and genitals.4 The patient was successfully treated with b.i.d. application of diflorasone (Apexicon, Maxiflor, Psorcon) ointment, a relatively powerful (Class 2) topical steroid that is seldom used on the face. The diflorasone was tapered down over a period of two weeks and was gradually replaced by tacrolimus (Hecoria, Protopic) ointment, a topical macrolide immunosuppressant.5 She was also advised to wash her face twice daily with OTC ketoconazole (Nizoral) shampoo to reduce the numbers of M. furfur yeast. Within three weeks, the patient was able to stop all medications.

Since a permanent cure is not available, treatment of seborrheic dermatitis usually focuses on control with a combination of topical steroids and such antifungal measures as imidazole creams or shampoos used as face wash.

Seborrheic dermatitis is usually obvious clinically, but as this case illustrates, it can be complicated by patient and provider misdiagnosis.

CASE #2

Chronic cutaneous lupus

Facial rashes, an extremely common complaint, are typically diagnosed and treated with relative ease. But there is a bewildering and extensive range of possible explanations for facial complaints that falls outside the usual and customary. For obvious reasons, patients are often very concerned about their appearance, especially early on when a clear diagnosis and effective treatment are elusive.

By the time this patient was examined by dermatology, both sides of her face were quite red. Discrete and confluent blanchable papules, nodules, and plaques (many of which were polycyclic) with clearing and slightly atrophic centers were noted. Little if any scale was seen, although the

patient reported scrubbing fi ne scale away each morning and night. Her lesions were confined to sun-exposed skin and stopped abruptly at her neckline.

The patient reported no fever, joint pain, or malaise and denied any personal or family history of similar problems.

Strongly suspecting lupus, the provider obtained a 3 mm punch biopsy specimen from the peripheral face and submitted it to pathology with a working differential of lupus vs. polymorphous light eruption. At the same time, an additional specimen was obtained for separate processing

Lesions of subacute cutaneous lupus erythematosus seldom involve the follicle, do not scar, and tend to be transitory. and sent to pathology in Michel’s transport medium for direct immunofluorescence studies.

A dermatopathologist was able to verify the diagnosis of probable subacute cutaneous lupus erythematosus (SCLE), a clinically distinct form of lupus first described in 1979.6,7 Pathology showed vacuolar interface dermatitis but no follicular plugging, basement membrane thickening, or heavy lymphoid aggregates, which might have suggested discoid lupus (DLE).

Differential item functioning studies were positive for a dustlike particulate deposition of immunoglobulin G in epidermal nuclei, also consistent with what is seen in approximately one third of individuals with SCLE.8 SCLE is mostly found in white women aged 15 to 40 years. Lesions can be scaly and evolve as polycyclic annular lesions with clearing centers.6 Unlike DLE, SCLE lesions seldom involve the follicle, do not scar, and tend to be transitory. However, patients with SCLE can have concomitant DLE in other locations.

As seen in this case, photosensitivity is a prominent feature in the majority of individuals with SCLE. Bloodwork from this patient demonstrated a positive ANA, as is the case approximately 80% of the time with SCLE.9 The rest of this patient’s lupus profi le is pending, but a positive Ro/SSA antigen is expected.

Clinically, most cases of SCLE run a mild course and respond to sun protection and the use of antimalarials.

Topical steroids are usually not necessary but can be useful for local control.10 Continues on page 68

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MAY 2012 67

CME CE

Dermatologic Look-Alikes

Drugs that can trigger an eruption similar to that of SCLE include hydrochlorothiazide, ACE inhibitors, and calcium channel blockers, among others.

Besides the differential mentioned above, other items to be considered include erythema multiforme, psoriasis, tertiary syphilis, and dermatomyositis.

The woman in this case will be managed by dermatology and rheumatology, given her potential for systemic involvement, which can include such overlap syndromes as Sjögren’s. It is possible that she will have to be treated with multiple systemic medications in the event of nonresponse to conservative treatment. Because of the role sun exposure played in the genesis of the patient’s disease, she was advised to consider changing careers. ■ Mr. Monroe is a physician assistant specializing in dermatology at Dawkins Dermatology in Oklahoma City.

“Sorry, Bad Cop’s already been here, and he took your donut.”

References 1. Medscape Reference. Seborrheic dermatitis. Available at emedicine .medscape.com/article/1108312-overview.

2. James WD, Berger TG, Elston DM. Seborrheic dermatitis. In: Andrews’ Diseases of the Skin: Clinical Dermatology. 10th ed. Philadelphia, Pa.: Saunders-Elsevier; 2006:191-193 3. Belew PW, Rosenberg EW, Jennings BR. Activation of the alternative pathway of complement by Malassezia ovalis (Pityrosporum ovale).

Mycopathologia. 1980;70:187-191.

4. Green CA, Farr PM, Shuster S. Treatment of seborrhoeic dermatitis with ketoconazole: II. Response of seborrhoeic dermatitis of the face, scalp and trunk to topical ketoconazole. Br J Dermatol. 1987;116:217-221.

“So near and yet so far!”

rolimus ointment in the treatment of seborrheic dermatitis. J Am Acad Dermatol. 2003;49:145-147.

6. James WD, Berger TG, Elston DM. Connective tissue diseases. In: Andrews’ Diseases of the Skin: Clinical Dermatology. 10th ed. Philadelphia, Pa.: Saunders-Elsevier; 2006:157-166.

7. Sontheimer RD. Subacute cutaneous lupus erythematosus: 25-year evolution of a prototypic subset (subphenotype) of lupus erythematosus defined by characteristic cutaneous, pathological, immunological, and genetic findings. Autoimmun Rev. 2005;4:253-263.

8. Medscape Reference. Subacute cutaneous lupus erythematosus (SCLE).

Available at emedicine.medscape.com/article/1065657-overview.

9. Fabbri P, Cardinali C, Giomi B, Caproni M. Cutaneous lupus erythematosus: diagnosis and management. Am J Clin Dermatol. 2003;4:449-465.

10. Wozniacka A, McCauliffe DP. Optimal use of antimalarials in treating cutaneous lupus erythematosus. Am J Clin Dermatol. 2005;6:1-11.

All electronic documents accessed April 15, 2012.

68 THE CLINICAL ADVISOR • MAY 2012 • www.ClinicalAdvisor.com

“It’s a magic potion that makes everything you say interesting.”

© The New Yorker Collection 2012 from cartoonbank.com. All Rights Reserved.

5. Meshkinpour A, Sun J, Weinstein G. An open pilot study using tac-

NPSecure® Because Your Own Malpractice Policy Is Your Best Protection. n

Competitive Premiums

n

Occurrence Policy Available In 50 States

n

Portable, Seamless Protection Wherever You Work Or Volunteer

n

No Conflict Of Interest In The Event Of A Claim Involving Multiple Providers

n

Coverage For All Specialties Including High Risk Classes

n

Employed, Self­Employed & Student Coverage Options

n

HIPAA Coverage

n

License Protection Coverage

n

Defense Expenses Coverage

99 Hudson Street, 12th Floor New York, NY 10013­2815 Tel: 1­800­221­4904 Email: np@cmfgroup.com VISA/MasterCard

www.NPSecure.com

®

PA Protect Because Your Own Malpractice Policy Is Your Best Protection. n

Portable, Seamless Protection Wherever You Work Or Volunteer

n

No Conflict Of Interest In The Event Of A Claim Involving Multiple Providers

n

Full Time, Part Time & Moonlighting Coverage Options

n

Occurrence Policy

n

Claims Made Conversion To Occurrence Available (No Tail)

n

HIPAA Coverage

n

License Protection Coverage

n

Defense Expenses Coverage

n

10% AAPA­Endorsed Risk Management Credit

11 South LaSalle Street, Suite 2300 Chicago, IL 60603­1333 Tel: 1­877­356­2272 Fax: 312­578­9556 Email: pa@cmfgroup.com VISA/MasterCard

www.PA­Protect.com

CE

POSTTEST Expiration date: May 2013

Nurse Practitioner Associates for Continuing Education (NPACE) is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s Commission on Accreditation.

The Nurse Practitioner Associates for Continuing Education designates this educational activity for a maximum of 1.0 contact hours of credit. Participants should only claim credit commensurate with the extent of their participation in the activity. Posttests must be completed and submitted online. NPs may register at no charge at www.myCME.com.You must receive a score of 70% or better on each test taken to obtain credit.

CREDITS: 0.5

CREDITS: 0.5

Feature

Dermatology Clinic

Dermatologic Look-Alikes

page 23

page 59

page 65

HAART meds: Implications for the older adult patient

Erythema dyschromicum perstans

Seborrheic dermatitis

1. The activity of some protease inhibitors (PIs) is boosted by the addition of which medication to the regimen? a. Raltegravir (ISENTRESS) b. Abacavir (Ziagen) c. Ritonavir (Norvir) d. Enfuvirtide (Fuzeon) 2. What is the most common adverse effect associated with highly active antiretroviral therapy (HAART)? a. Immune suppression b. Metabolic abnormalities c. Nephrotoxicity d. Esophagitis 3. Some of the strongest data regarding the association of HAART with bone mineral density reductions have been observed with which medication? a. Abacavir b. Zidovudine (Retrovir) c. Tenofovir (Viread) d. Lopinavir (Kaletra) 4. Which medication is contraindicated in a patient taking PIs? a. Proton pump inhibitor b. Digoxin c. Beta blocker d. Erectile dysfunction drug

1. What is a universal finding in active 1. How is lichen planus usually systemic lupus erythematosus lesions? distinguished clinically? a. Vacuolar interface dermatitis a. Waxy dome-shaped, umbilicated b. Well-demarcated areas of erythema papules c. Plaques and scaling with lichenification b. Flat-topped papules and plaques d. Scattered macules with greasy c. Cauliflower-shaped lesions with appearance petechiae d. Solid, firm, thick plaques with 2. What OTC medication is used to scaling reduce the numbers of Malassezia 2. What is the treatment for erythema furfur yeast? dyschromicum perstans? a. Nystatin cream a. UV light therapy b. Clotrimazole topical solution b. Chemical peels c. Ketoconazole (Nizoral) shampoo c. Cryosurgery d. Topical corticosteroid d. There is no effective therapy Chronic cutaneous lupus Cutaneous angiosarcoma 3. Which feature is suggestive of discoid 3. What is a risk factor for angiosarcoma (AS)? a. Fair skin b. History of radiation therapy c. Older age d. Previous severe skin injury 4. Which sign is usually indicative of metastases of AS? a. Lymph node enlargement b. Systemic bleeding c. Increasing tumor depth d. Satellite lesions

TO TAKE THE POSTTEST please go to ClinicalAdvisor.com/CMEFeatureMay2012

70 THE CLINICAL ADVISOR • MAY 2012 • www.ClinicalAdvisor.com

lupus erythematosus? a. Follicular plugging b. Basement membrane thickening c. Heavy lymphoid aggregates d. All of the above 4. Which drug class can trigger an eruption similar to that of subacute cutaneous lupus erythematosus? a. Calcium channel blockers b. Tricyclic antidepressants c. Proton pump inhibitors d. Statins

TO TAKE THE POSTTEST please go to ClinicalAdvisor.com/DermMay2012

CME

POSTTEST Expiration date: May 2013

This program has been reviewed and is approved for a maximum of 1 hour of AAPA Category I CME credit by the Physician Assistant Review Panel. Approval is valid for one year from the issue date of May 2012. Participants may submit the self-assessment at any time during that period.

This program was planned in accordance with AAPA’s CME Standards for Enduring Material Programs and for Commercial Support of Enduring Material Programs.

Posttests must be completed and submitted online. PAs may register at no charge at www.myCME.com. To obtain 1.0 hour of AAPA Category I CME credit, you must receive a score of 70% or better on each test taken.

CREDITS: 0.5

CREDITS: 0.5

Feature

Dermatology Clinic

Dermatologic Look-Alikes

page 23

page 59

page 65

HAART meds: Implications for the older adult patient

Erythema dyschromicum perstans

Seborrheic dermatitis

1. The activity of some protease inhibitors (PIs) is boosted by the addition of which medication to the regimen? a. Raltegravir (ISENTRESS) b. Abacavir (Ziagen) c. Ritonavir (Norvir) d. Enfuvirtide (Fuzeon) 2. What is the most common adverse effect associated with highly active antiretroviral therapy (HAART)? a. Immune suppression b. Metabolic abnormalities c. Nephrotoxicity d. Esophagitis 3. Some of the strongest data regarding the association of HAART with bone mineral density reductions have been observed with which medication? a. Abacavir b. Zidovudine (Retrovir) c. Tenofovir (Viread) d. Lopinavir (Kaletra) 4. Which medication is contraindicated in a patient taking PIs? a. Proton pump inhibitor b. Digoxin c. Beta blocker d. Erectile dysfunction drug

1. What is a universal finding in active 1. How is lichen planus usually systemic lupus erythematosus lesions? distinguished clinically? a. Vacuolar interface dermatitis a. Waxy dome-shaped, umbilicated b. Well-demarcated areas of erythema papules c. Plaques and scaling with lichenification b. Flat-topped papules and plaques d. Scattered macules with greasy c. Cauliflower-shaped lesions with appearance petechiae d. Solid, firm, thick plaques with 2. What OTC medication is used to scaling reduce the numbers of Malassezia 2. What is the treatment for erythema furfur yeast? dyschromicum perstans? a. Nystatin cream a. UV light therapy b. Clotrimazole topical solution b. Chemical peels c. Ketoconazole (Nizoral) shampoo c. Cryosurgery d. Topical corticosteroid d. There is no effective therapy Chronic cutaneous lupus Cutaneous angiosarcoma 3. Which feature is suggestive of discoid 3. What is a risk factor for angiosarcoma (AS)? a. Fair skin b. History of radiation therapy c. Older age d. Previous severe skin injury 4. Which sign is usually indicative of metastases of AS? a. Lymph node enlargement b. Systemic bleeding c. Increasing tumor depth d. Satellite lesions

TO TAKE THE POSTTEST please go to ClinicalAdvisor.com/CMEFeatureMay2012

70 THE CLINICAL ADVISOR • MAY 2012 • www.ClinicalAdvisor.com

lupus erythematosus? a. Follicular plugging b. Basement membrane thickening c. Heavy lymphoid aggregates d. All of the above 4. Which drug class can trigger an eruption similar to that of subacute cutaneous lupus erythematosus? a. Calcium channel blockers b. Tricyclic antidepressants c. Proton pump inhibitors d. Statins

TO TAKE THE POSTTEST please go to ClinicalAdvisor.com/CMEFeatureMay2012

Available at myCME.com/UMDNJ NEW for 2011-2012 To listen on the go, download audio files to your MP3 player or burn them to a CD

PANCE/PANRE

“Regime change is never easy, dear.”

ONLINE REVIEW COURSE Q

Convenient: Study where and when you want. Practice examination questions at the end of each module.

Download all slides and handouts to print or review.

Q

Comprehensive: All topics on the NCCPA examination blueprint are covered in more than 27 hours of instruction. Self-reported 98.6% pass rate.

Q

Cost-effective: Only $349 for all 5 modules or $99 for an individual module.

DELIVERED VIA 5 MODULES FOR EASY REVIEW —EACH MODULE IS INDIVIDUALLY ACCREDITED —ACCESS AT MYCME.COM/UMDNJ

© The New Yorker Collection 2010 from cartoonbank.com. All Rights Reserved.

“Make it look like natural selection.”

Module 1

Cardiology/EKG Review

Module 2

Pulmonology, Pediatrics, Ophthalmology, Otorhinolaryngology

Module 3

Orthopedics, Neurology, Psychiatry

Module 4

Infectious Disease, Gastroenterology, Dermatology

Module 5

Reproductive System, Endocrinology, Genitourinary System, Hematology

ACCREDITATION INFORMATION This program has been reviewed and is approved for a maximum of 27.25 hours of AAPA Category 1 CME credit by the Physician Assistant Review Panel. Approval is valid for one year from the issue date of October 17, 2011. Participants may submit the self-assessment at any time during that period.

This program was planned in accordance with the AAPA’s CME Standards for Enduring Material Programs and for Commercial Support of Enduring Material Programs. This program has been planned without commercial support.

Developed by

Posted on

Sponsored by

“The knuckle sandwich looks good.”

Scan here to learn more

For advertising information, contact: Russell Johns Associates, LLC 1001 S Myrtle Ave, #7, Clearwater, FL 33756 Phone: 877.394.1388 or 727.443.7667 • Fax: 727.445.9380 • E-mail: ca@russelljohns.com

PA WANTED

CLASSIFIEDS PA WANTED

Champlain Valley Heart Center, located in Plattsburgh, NY, is seeking a Staff PA for our Cardiothoracic Surgical program.

Veterans Affairs Ann Arbor Healthcare System Physician’s Assistant (Gastroenterology) The VA Ann Arbor Healthcare System is looking for a Physician’s Assistant (PA) within Medicine Service’s Gastroenterology department.

The role of Physician Assistant is to include, but not limited to, functioning as an expert consultant, maintaining current knowledge of practice standards and guidelines related to Gastroenterology and specific to their Gastroenterology subspecialties; including general gastroenterology, general hepatology, evaluation and treatment of patients with chronic hepatitis B and/or C, pre-operative assessment for endoscopic procedures, and inflammatory bowel disease care. Full-time/perm.

Performs new patient Gastroenterology Consultation and follow-up Gastroenterology visits in both Gastroenterology and Liver clinics, as well as telephone/video conferencing follow-up visits and collaborates as identified with Gastroenterology Staff.

Performs oversight of Gastroenterology studies, appropriate scheduling of staff and patients, patient flow, safety, quality management. Participates in Peer Review.

All interested applicants please go to http://www.usajobs.gov/GetJob/ViewDetails/313157700 to apply for this position.

Questions about this job: Rhi Seelbinder Phone: (734) 845-3464 Ann Arbor, MI 48105 Email: rhiannon.seelbinder@va.gov

PA WANTED

The heart surgical program at CVPH was begun in 2005 and continues to grow, surrounded by the very best in advanced technology. We performed 739 PCI’s and 130 Open Hearts in 2011; an additional 100+ general thoracic procedures are performed annually, with anticipated growth. Our cardiology and cardiac surgical services have received numerous national and state awards and recognitions for both clinical excellence and outcomes.

Join the CVPH cardiothoracic surgical team at CVPH! Interested Staff PA candidates must have at least two to three years of cardiac surgical experience with the desire to become proficient with Endoscopic Vein Harvesting (EVH), surgical first-assisting, and to work collaboratively as part of the Cardiac Surgery team to provide excellent patient care.

With a generous annual compensation and benefits package, we’re very competitive with other cardiac surgical programs.

The benefit package includes relocation up to $10K. In addition, CVPH will offer either a sign-on bonus or up to $20,000 in loan forgiveness for a 2-year employment commitment.

Plattsburgh is a picturesque community of 38,000 located on Lake Champlain and at the foothills of the Adirondack Mountains.

We live where others vacation!

Contact: Becky Larkin, CVPH Medical Center 75 Beekman Street • Plattsburgh, NY 12901 Phone: 518-314-3025 • Email: rlarkin@cvph.org Website: www.cvph.org, select “Careers” in upper left column.

MEDICAL EDUCATION

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • MAY 2012 73

CLASSIFIEDS NP WANTED

For advertising information, contact: Russell Johns Associates, LLC 1001 S Myrtle Ave, #7, Clearwater, FL 33756 Phone: 877.394.1388 or 727.443.7667 • Fax: 727.445.9380 • E-mail: ca@russelljohns.com

PA/NP WANTED

MEDICAL EDUCATION

VACATION CME

PA/ARNP Walk-in clinic located near Jupiter Island offering competitive compensation and benefits. Supported by well trained licensed professional staff. Our practice model is walk-in urgent care and family medicine appointments. Applicants should have a minimum of 2 years experience in an urgent care setting and be comfortable with minor surgical procedures as well as reading x-rays. The clinic is spacious and well-equipped. Please submit your resume via email or fax.

You may visit our website at www.helixcares.com Skills: Current Florida License • Minimum 2 years experience in urgent care • Suturing • Minor surgical procedures • Work comp and occmed experience • Familiar with wet reads

AAFP PRESCRIBED CREDIT Live Seminars - 15 Prescribed Credits New Drug Update DVD 10 Prescribed Credits - Anytime - Anywhere!

www.universitylearning.com For 10% off any ULS seminar use Promo Code: CAD12 Can’t be combined with any other discounts.

1-800-940-5860

Additional Information: Masters or Graduate Degree BJ Stone, GM 750 S Federal Hwy, Deerfield Beach, FL 33441 954-421-8181, ex. 226 • Fax: 954-426-2967 bstone@mydoublehelices.com

Family Nurse Practitioner Positions available in the following areas: Family Practice/Pediatrics, Women’s Health, Prenatal, Adult Care and Homeless Population.

The Children’s Clinic, Serving Children and Their Families is a non-profit community clinic serving lowincome patients at eight sites in Long Beach and Bellflower. We have a strong emphasis on compassionate patient centered care and are seeking a Nurse Practitioner who is mission driven and committed to serving this population. We are focused on disease management and participate in the BPHC Health Disparities Collaborative for Diabetes. Epic EMR implemented successfully. We are a National Health Service Corps (NHSC) loan repayment site.

PA WANTED

Phoenix Joint Replacement Orthopaedic needs PA-C. 20 yr+ Solo MD needs PA to assist in Surgery and Office while maintaining the high level of excellence that our doctor has established.

Competitive salary, pension plan and benefits.

Contact:

laura@rockowitzortho.com

MEDICAL EDUCATION

Principal Responsibilities Under the supervision of a physician, Nurse Practitioner assesses patients’ medical/surgical conditions; administers treatments; facilitates communication; assists as directed within parameters as outlined and utilizes the protocols for all independent and interdependent nursing practice. Services may include but are not limited to initial health screening to determine client’s status, acute care needs, and diagnostic impression, linkage to appropriate levels of mental health and physical health care, provides support and follow up care as needed.

Minimum Requirements Graduation from an accredited nurse practitioner program with an MSN or MN and current licensure as an RN Nurse Practitioner in California. Spanish Preferred.

Classified Advertising (877) 394-1388 Fax: (727) 445-9380 Email: ca@russelljohns.com

Visit:

Demystifying Emergency Medicine 8 Hour DVD DVD 1: Secrets of Lab Medicine DVD 2: The Pulmonary Patient and CXR DVD 3: Chest Pain and Advanced 12 Lead EKG DVD 4: Common Emergency Medicine Complaints

Application Process Interested candidates are invited to apply by sending CV/resume with salary requirements to: Dnoble@memorialcare.org or Fax: (562) 933-0538.

EOE M/F/D/V. For more information, please visit web site: www.thechildrensclinic.org

The BEST Board Review Course on the Planet, Coming Live 2013!

Deadline: Applications will be accepted until position is filled.

Pharmacology, GI & Cardiology

Board Review DVDs Now Available:

*Please feel free to post or forward this information to interested person*

Advanced Life Support 5 Hour DVD

Free 64 GB iPad 3 Wi-Fi CME Package

DVD 1: Medical Emergencies DVD 2: Cardiac Pharmacology DVD 3: Understanding PALS DVD 4: Demystifying ALS: Understanding Beyond Algorithms

74 THE CLINICAL ADVISOR • MAY 2012 • www.ClinicalAdvisor.com